Therapeutic compounds and uses thereof

ABSTRACT

and to salts thereof, wherein R—R4 of formula (I) and R5-R6 of formula (II) have any of the values defined herein, and compositions and uses thereof. The compounds are useful as inhibitors of CBP and/or EP300. Also included are pharmaceutical compositions comprising a compound of formula (I) of formula (II), or a pharmaceutically acceptable salt thereof, and methods of using such compounds and salts in the treatment of various CBP and/or EP300-mediated disorders.

PRIORITY OF INVENTION

This application is a continuation of U.S. patent application Ser. No.16/198,597, filed 21 Nov. 2018, which is a continuation of InternationalApplication No. PCT/US2017/034320, filed 24 May 2017, which claimspriority from International Patent Application PCT/CN2016/083124, filed24 May 2016. The entire content of the applications referenced above arehereby incorporated by reference herein.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been filedelectronically in ASCII format and is hereby incorporated by referencein its entirety. Said ASCII copy, created on Feb. 27, 2019, is named01076_033US1_SL.txt and is 7,162 bytes in size.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds useful as inhibitors ofCBP/EP300 and methods of treating cancer using such inhibitors.

BACKGROUND OF THE INVENTION

Chromatin is a complex combination of DNA and protein that makes upchromosomes. It is found inside the nuclei of eukaryotic cells and isdivided between heterochromatin (condensed) and euchromatin (extended)forms. The major components of chromatin are DNA and proteins. Histonesare the chief protein components of chromatin, acting as spools aroundwhich DNA winds. The functions of chromatin are to package DNA into asmaller volume to fit in the cell, to strengthen the DNA to allowmitosis and meiosis, and to serve as a mechanism to control expressionand DNA replication. The chromatin structure is controlled by a seriesof post-translational modifications to histone proteins, notablyhistones H3 and H4, and most commonly within the “histone tails” whichextend beyond the core nucleosome structure. Histone tails tend to befree for protein-protein interaction and are also the portion of thehistone most prone to post-translational modification. Thesemodifications include acetylation, methylation, phosphorylation,ubiquitinylation, and SUMOylation. These epigenetic marks are writtenand erased by specific enzymes that place the tags on specific residueswithin the histone tail, thereby forming an epigenetic code, which isthen interpreted by the cell to allow gene specific regulation ofchromatin structure and thereby transcription.

Of all classes of proteins, histones are amongst the most susceptible topost-translational modification. Histone modifications are dynamic, asthey can be added or removed in response to specific stimuli, and thesemodifications direct both structural changes to chromatin andalterations in gene transcription. Distinct classes of enzymes, namelyhistone acetyltransferases (HATs) and histone deacetylases (HDACs),acetylate or de-acetylate specific histone lysine residues (Struhl K.,Genes Dev., 1989, 12, 5, 599-606).

Bromodomains, which are approximately 110 amino acids long, are found ina large number of chromatin-associated proteins and have been identifiedin approximately 70 human proteins, often adjacent to other proteinmotifs (Jeanmougin F., et al., Trends Biochem. Sci., 1997, 22, 5,151-153; and Tamkun J. W., et al., Cell, 1992, 7, 3, 561-572).Interactions between bromodomains and modified histones may be animportant mechanism underlying chromatin structural changes and generegulation. Bromodomain-containing proteins have been implicated indisease processes including cancer, inflammation and viral replication.See, e.g., Prinjha et al., Trends Pharm. Sci., 33(3):146-153 (2012) andMuller et al., Expert Rev., 13(29):1-20 (September 2011).

Cell-type specificity and proper tissue functionality requires the tightcontrol of distinct transcriptional programs that are intimatelyinfluenced by their environment. Alterations to this transcriptionalhomeostasis are directly associated with numerous disease states, mostnotably cancer, immuno-inflammation, neurological disorders, andmetabolic diseases. Bromodomains reside within key chromatin modifyingcomplexes that serve to control distinctive disease-associatedtranscriptional pathways. This is highlighted by the observation thatmutations in bromodomain-containing proteins are linked to cancer, aswell as immune and neurologic dysfunction. Hence, the selectiveinhibition of bromodomains across a specific family, such as theselective inhibition of a bromodomain of CBP/EP300, creates variedopportunities as novel therapeutic agents in human dysfunction.

There is a need for treatments for cancer, immunological disorders, andother CBP/EP300 bromodomain related diseases.

SUMMARY OF THE INVENTION

Compounds of Formula (I) or Formula (II)

One aspect is a compound of formula (I) or formula (II):

or a salt thereof, wherein:

R¹ is hydrogen, —NR^(a)R^(b), C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, and3-8 membered carbocyclyl, wherein each C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, and 3-8 membered carbocyclyl is optionally substituted withone or more groups independently selected from oxo, halo, amino,hydroxyl, C₁₋₆alkoxy, and C₁-C₆ alkyl that is optionally substitutedwith one or more groups independently selected from oxo and halo;

each R² is independently selected from the group consisting ofC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(t))₂,—CN, —C(O)—N(R^(t))₂, —O—R, —O—C(O)—R^(t), —C(O)—R, and —C(O)—O—R,wherein any C₁₋₆alkyl, C₂₋₆alkenyl, and C₂₋₆alkynyl is optionallysubstituted with one or more halo;

R³ is 3-12 membered carbocycle or a 3-12 membered heterocycle, whereineach 3-12 membered carbocycle and 3-12 membered heterocycle of R³ isoptionally substituted with one or more groups R^(u);

Y is O or N(R^(c));

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3, or 4;

p is 0, 1, 2, 3, or 4;

ring A is a fused ring that is selected from the group consisting ofbenzo and a 6-membered heterocycle;

each R⁴ is independently selected from the group consisting ofC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(w))₂,—CN, —C(O)—N(R^(w))₂, —O—R^(w), —O—C(O)—R^(w), —C(O)—R^(x), and—C(O)—O—R^(w), wherein any C₁₋₆alkyl, C₂₋₆alkenyl, and C₂₋₆alkynyl isoptionally substituted with one or more oxo or halo;

each R⁵ is independently selected from the group consisting ofC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(w))₂,—CN, —C(O)—N(R^(w))₂, —O—R^(w), —O—C(O)—R^(w), —C(O)—R^(x), and—C(O)—O—R^(w), wherein any C₁₋₆alkyl, C₂₋₆alkenyl, and C₂₋₆alkynyl isoptionally substituted with one or more oxo or halo;

R⁶ is —N(R^(z))—C(O)—R^(x), 3-12 membered carbocycle, or a 3-12 memberedheterocycle, wherein each 3-12 membered carbocycle and 3-12 memberedheterocycle of R⁶ is optionally substituted with one or more groups R;

X is N or C(R⁷);

R⁷ is H or C₁-C₆ alkyl that is optionally substituted with one or moregroups independently selected from oxo and halo;

each R^(a) and R^(b) is independently selected from hydrogen,C₁₋₆-alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, 3-12 membered carbocyclyl, and3-12 membered heterocyclyl, wherein each C₁₋₆-alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, 3-12 membered carbocyclyl, and 3-12 membered heterocyclylis optionally substituted with one or more groups independently selectedfrom oxo, halo, amino, hydroxyl, C₁₋₆alkoxy, 3-12 membered carbocyclyl,3-12 membered heterocyclyl, and C₁-C₆ alkyl that is optionallysubstituted with one or more groups independently selected from oxo andhalo; or R^(a) and R^(b) are taken together with the nitrogen to whichthey are attached to form a heterocyclyl that is optionally substitutedwith one or more groups independently selected from oxo, halo andC₁₋₃alkyl that is optionally substituted with one or more groupsindependently selected from oxo and halo;

R^(c) is hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, or C₂₋₆alkynyl, wherein eachC₁₋₆alkyl, C₂₋₆alkenyl, and C₂₋₆alkynyl is optionally substituted withone or more groups independently selected from oxo and halo;

-   -   each R is independently selected from hydrogen, C₁₋₆-alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, 3-12 membered carbocyclyl, and 3-12        membered heterocyclyl, wherein each C₁₋₆alkyl, C₂-6alkenyl,        C₂₋₆alkynyl, 3-12 membered carbocyclyl, and 3-12 membered        heterocyclyl is optionally substituted with one or more groups        independently selected from oxo, halo, amino, hydroxyl,        C₁₋₆alkoxy, 3-12 membered carbocyclyl, 3-12 membered        heterocyclyl, and C₁-C₆ alkyl that is optionally substituted        with one or more groups independently selected from oxo and        halo; or two R^(t) are taken together with the nitrogen to which        they are attached to form a 3-12 membered heterocyclyl that is        optionally substituted with one or more groups independently        selected from oxo, halo and C₁₋₃alkyl that is optionally        substituted with one or more groups independently selected from        oxo and halo;

each R^(u) of is independently selected from oxo, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, 3-12 membered carbocyclyl, 3-12 memberedheterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(w))₂,—S(O)—N(R^(w))₂, —S(O)₂—N(R^(v))₂, —O—R^(w), —S—R^(w), —O—C(O)—R^(w),—O—C(O)—O—R^(w), —C(O)—R^(w), —C(O)—O—R^(w), —S(O)—R^(w), —S(O)₂—R^(w),—O—C(O)—N(R^(w))₂, —N(R^(w))—C(O)—OR^(w), —N(R^(w))—C(O)—N(R^(w))₂,—N(R^(v))—C(O)—R^(v), —N(R^(v))—S(O)—R^(v), —N(R^(v))—S(O)₂—R^(v),—N(R^(v))—S(O)—N(R^(v))₂, and —N(R^(v))—S(O)₂—N(R^(v))₂, wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, 3-12 membered carbocyclyl, 3-12membered heterocyclyl, is optionally substituted with one or more groupsindependently selected from oxo, halo, —NO₂, —N(R^(v))₂, —CN,—C(O)—N(R^(v))₂, —S(O)—N(R^(v))₂, —S(O)₂—N(R^(v))₂, —O—R^(w), —S—R^(w),—O—C(O)—R^(w), —C(O)—R^(w), —C(O)—O—R^(w), —S(O)—R^(w), —S(O)₂—R^(w),—C(O)—N(R^(v))₂, —N(R^(v))—C(O)—R^(v), —N(R^(v))—S(O)—R^(v),—N(R^(v))—S(O)₂—R^(v), 3-12 membered carbocycle, and C₁₋₆alkyl that isoptionally substituted with one or more groups independently selectedfrom oxo and halo;

each R^(v) is independently selected from hydrogen, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, 3-12 membered carbocyclyl, and3-12 membered heterocyclyl, wherein each C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆alkoxy, carbocyclyl, and heterocyclyl is optionallysubstituted with one or more groups independently selected from oxo,halo, amino, hydroxyl, C₁₋₆alkoxy, 3-12 membered carbocyclyl, 3-12membered heterocyclyl, and C₁-C₆ alkyl that is optionally substitutedwith one or more groups independently selected from oxo and halo; or twoR^(w) are taken together with the nitrogen to which they are attached toform a 3-12 membered heterocyclyl that is optionally substituted withone or more groups independently selected from oxo, halo and C₁₋₃alkylthat is optionally substituted with one or more groups independentlyselected from oxo and halo;

each R^(w) is independently selected from hydrogen, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, 3-12 membered carbocyclyl, and 3-12 memberedheterocyclyl, wherein each C₁₋₆alkyl, C₂-6alkenyl, C₂₋₆alkynyl, 3-12membered carbocyclyl, and 3-12 membered heterocyclyl is optionallysubstituted with one or more groups independently selected from oxo,halo, amino, hydroxyl, C₁₋₆alkoxy, 3-12 membered carbocyclyl, 3-12membered heterocyclyl, and C₁-C₆ alkyl that is optionally substitutedwith one or more groups independently selected from oxo and halo; or twoR^(t) are taken together with the nitrogen to which they are attached toform a heterocyclyl that is optionally substituted with one or moregroups independently selected from oxo, halo and C₁₋₃alkyl that isoptionally substituted with one or more groups independently selectedfrom oxo and halo;

each R^(x) of is independently selected from oxo, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, 3-12 membered carbocyclyl, 3-12 memberedheterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(y))₂, —CN, —C(O)—N(R^(y))₂,—S(O)—N(R^(y))₂, —S(O)₂—N(R^(y))₂, —O—R^(y), —S—R^(y), —O—C(O)—R^(y),—O—C(O)—O—R^(y), —C(O)—R^(y), —C(O)—O—R^(y), —S(O)—R^(y), —S(O)₂—R^(y),—O—C(O)—N(R^(y))₂, —N(R^(y))—C(O)—R^(y), —N(R^(y))—C(O)—N(R^(y))₂,—N(R^(y))—C(O)—R^(y), —N(R^(y))—S(O)—R^(y), —N(R^(y))—S(O)₂—R^(y),—N(R^(y))—S(O)—N(R^(y))₂, and —N(R^(y))—S(O)₂—N(R^(y))₂, wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, 3-12 membered carbocyclyl, and 3-12membered heterocyclyl, is optionally substituted with one or more groupsindependently selected from oxo, halo, —NO₂, —N(R^(y))₂, —CN,—C(O)—N(R^(y))₂, —S(O)—N(R^(y))₂, —S(O)₂—N(R^(y))₂, —O—R^(y), —S—R^(y),—O—C(O)—R^(y), —C(O)—R^(y), —C(O)—O—R^(y), —S(O)—R^(y), —S(O)₂—R^(y),—C(O)—N(R^(y))₂, —N(R^(y))—C(O)—R^(y), —N(R^(y))—S(O)—R^(y),—N(R^(y))—S(O)₂—R^(y), 3-12 membered carbocycle, and C₁₋₆alkyl that isoptionally substituted with one or more groups independently selectedfrom oxo and halo;

each R^(y) is independently selected from hydrogen, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, 3-12 membered carbocyclyl, and3-12 membered heterocyclyl, wherein each C₁-6alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆alkoxy, 3-12 membered carbocyclyl, and 3-12 memberedheterocyclyl is optionally substituted with one or more groupsindependently selected from oxo, halo, amino, hydroxyl, C₁₋₆alkoxy, 3-12membered carbocyclyl, 3-12 membered heterocyclyl, and C₁-C₆ alkyl thatis optionally substituted with one or more groups independently selectedfrom oxo and halo; or two R^(y) are taken together with the nitrogen towhich they are attached to form a 3-12 membered heterocyclyl that isoptionally substituted with one or more groups independently selectedfrom oxo, halo and C₁₋₃alkyl that is optionally substituted with one ormore groups independently selected from oxo and halo; and

each R^(z) is independently selected from hydrogen, C₁₋₆alkyl.

Another aspect includes a composition comprising a compound of formula(I) or formula (II) or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable adjuvant, carrier, or vehicle.

Another aspect includes a method for treating a CBP and/orEP300-mediated disorder in an animal comprising administering a compoundof formula (I) or formula (II) or a pharmaceutically acceptable saltthereof to the animal.

Another aspect includes a method for treating a CBP and/orEP300-mediated disorder in an animal, wherein the disorder is cancer,comprising administering a compound of formula (I) or formula (II) or apharmaceutically acceptable salt thereof to the animal.

Another aspect includes a method for treating a CBP and/orEP300-mediated disorder in an animal, wherein the disorder is a fibroticdisease, comprising administering a compound of formula (I) or formula(II) or a pharmaceutically acceptable salt thereof to the animal.

Another aspect includes a method for treating a CBP and/orEP300-mediated disorder in an animal, wherein the disorder is a fibroticlung disease, comprising administering a compound of formula (I) orformula (II) or a pharmaceutically acceptable salt thereof to theanimal.

Another aspect includes a compound of formula (I) or formula (II) or apharmaceutically acceptable salt thereof for use in medical therapy.

Another aspect includes a compound of formula (I) or formula (II) or apharmaceutically acceptable salt thereof for the prophylactic ortherapeutic treatment of a CBP and/or EP300-mediated disorder.

Another aspect includes the use of a compound of formula (I) or formula(II) or a pharmaceutically acceptable salt thereof to prepare amedicament for treating a CBP and/or EP300-mediated disorder in ananimal (e.g. a mammal such as a human).

Another aspect includes compounds for the study of CBP and/or EP300.

Another aspect includes synthetic intermediates and synthetic processesdisclosed herein that are useful for preparing a compound of formula (I)or formula (II) or a salt thereof.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. Outline of protocol for assaying CBP/p300 SMIs for inhibition ofprofibrotic gene induction by TGFβ.

DETAILED DESCRIPTION Definitions

Definitions and terms are described in more detail below. Chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed.

Unless otherwise stated, compounds of formula I or formula II includeenantiomeric, diastereomeric and geometric (or conformational) isomericforms of a given structure. For example, the R and S configurations foreach asymmetric center, Z and E double bond isomers, Z and Econformational isomers, single stereochemical isomers, as well asenantiomeric, diastereomeric, and geometric (or conformational) mixturesare included. Unless otherwise stated, all tautomeric forms ofstructures depicted herein are included. Additionally, unless otherwisestated, structures depicted herein are also meant to include compoundsthat differ only in the presence of one or more isotopically enrichedatoms. For example, compounds of formula I or formula II, wherein theindependent replacement or enrichment of one or more hydrogen bydeuterium or tritium, carbon by ¹³C- or ¹⁴C carbon, nitrogen by a ¹⁵Nnitrogen, sulfur by a ³³S, ³⁴S or ³⁶S sulfur, oxygen by a ¹⁷O or ¹⁸Ooxygen, or fluorine by a ¹F are included. Such compounds are useful, forexample, as analytical tools, as probes in biological assays, or astherapeutic agents.

Where a particular enantiomer is described, it may, in certainembodiments be provided substantially free of the correspondingenantiomer, and may also be referred to as “optically enriched.”“Optically-enriched,” as used herein, means that the mixture ofenantiomers is made up of a significantly greater proportion of oneenantiomer, and may be described by enantiomeric excess (ee %). Incertain embodiments, the mixture of enantiomers is made up of at leastabout 90% by weight of a given enantiomer (about 90% ee). In otherembodiments, the mixture of enantiomers is made up of at least about95%, 98% or 99% by weight of a given enantiomer (about 95%, 98% or 99%ee). Enantiomers and diastereomers may be isolated from racemic mixturesby any method known to those skilled in the art, includingrecrystallization from solvents in which one stereoisomer is moresoluble than the other, chiral high pressure liquid chromatography(HPLC), supercritical fluid chromatography (SFC), the formation andcrystallization of chiral salts, which are then separated by any of theabove methods, or prepared by asymmetric syntheses and optionallyfurther enriched. See, for example, Jacques et al., Enantiomers,Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen,et al., Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry ofCarbon Compounds (McGraw-Hill, N Y, 1962); Wilen, S. H. Tables ofResolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, Ind. 1972).

The term “heteroatom” means any atom independently selected from an atomother than carbon or hydrogen, for example, one or more of oxygen,sulfur, nitrogen, phosphorus or silicon (including any oxidized form ofnitrogen, sulfur, phosphorus or silicon; and the quaternized form of anynitrogen).

The terms “halo” and “halogen” as used herein refer to an atom selectedfrom fluorine (fluoro, —F), chlorine (chloro, —Cl), bromine (bromo, —Br)and iodine (iodo, —I).

The term “oxo” refers to ═O.

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation.

The term “carbocyclyl” used alone or as part of a larger moiety, refersto a saturated, partially unsaturated, or aromatic ring system having 3to 20 carbon atoms. In one embodiment, carbocyclyl includes 3 to 12carbon atoms (C₃-C₁₂). In another embodiment, carbocyclyl includesC₃-C₈, C₃-C₁₀ or C₅-C₁₀. In other embodiment, carbocyclyl, as amonocycle, includes C₃-C₈, C₃-C₆ or C₅-C₆. In another embodiment,carbocyclyl, as a bicycle, includes C₇-C₁₂. In another embodiment,carbocyclyl, as a spiro system, includes C₅-C₁₂. Examples of monocycliccarbocyclyls include cyclopropyl, cyclobutyl, cyclopentyl,1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,perdeuteriocyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl,1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl,cyclodecyl, cycloundecyl, phenyl, and cyclododecyl; bicycliccarbocyclyls having 7 to 12 ring atoms include [4,3], [4,4], [4,5],[5,5], [5,6] or [6,6] ring systems, for example bicyclo[2.2.1]heptane,bicyclo[2.2.2]octane, naphthalene, and bicyclo[3.2.2]nonane; and spirocarbocyclyls include spiro[2.2]pentane, spiro[2.3]hexane,spiro[2.4]heptane, spiro[2.5]octane and spiro[4.5]decane.

The term carbocyclyl includes aryl ring systems as defined herein. Theterm carbocycyl also includes cycloalkyl rings (e.g. saturated orpartially unsaturated mono-, bi-, or spiro-carbocycles).

The term “alkyl,” as used herein, refers to a saturated linear orbranched-chain hydrocarbon radical. In one embodiment, the alkyl radicalis one to eighteen carbon atoms (C₁-C₁₈). In other embodiments, thealkyl radical is C₀-C₆, C₀-C₅, C₀-C₃, C₁-C₁₂, C₁-C₁₀, C₁-C₈, C₁-C₆,C₁-C₅, C₁-C₄ or C₁-C₃. Co alkyl refers to a bond. Examples of alkylgroups include methyl (Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl (n-Pr,n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl, —CH(CH₃)₂), 1-butyl(n-Bu, n-butyl, —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (i-Bu, i-butyl,—CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃),2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl,—CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, heptyl, octyl, nonyl, decyl,undecyl and dodecyl.

The term “alkenyl,” as used herein, denotes a linear or branched-chainhydrocarbon radical with at least one carbon-carbon double bond. Analkenyl includes radicals having “cis” and “trans” orientations, oralternatively, “E” and “Z” orientations. In one example, the alkenylradical is two to eighteen carbon atoms (C₂-C₁₈). In other examples, thealkenyl radical is C₂-C₁₂, C₂-C₁₀, C₂-C₈, C₂-C₆ or C₂-C₃. Examplesinclude, but are not limited to, ethenyl or vinyl (—CH═CH₂), prop-1-enyl(—CH═CHCH₃), prop-2-enyl (—CH₂CH═CH₂), 2-methylprop-1-enyl, but-1-enyl,but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-diene,hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hexa-1,3-dienyl.

The term “alkynyl,” as used herein, refers to a linear or branchedhydrocarbon radical with at least one carbon-carbon triple bond. In oneexample, the alkynyl radical is two to eighteen carbon atoms (C₂-C₁₈).In other examples, the alkynyl radical is C₂-C₁₂, C₂-C₁₀, C₂-C₈, C₂-C₆or C₂-C₃. Examples include, but are not limited to, ethynyl (—C≡CH),prop-1-ynyl (—C≡CCH₃), prop-2-ynyl (propargyl, —CH₂C≡CH), but-1-ynyl,but-2-ynyl and but-3-ynyl.

The term “alkoxy” refers to a linear or branched radical represented bythe formula —OR in which R is alkyl, alkenyl, alkynyl or carbocycyl.Alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, andcyclopropoxy.

The term “haloalkyl,” as used herein, refers to an alkyl as definedherein that is substituted with one or more (e.g. 1, 2, 3, or 4) halogroups.

The term “aryl” used alone or as part of a larger moiety as in“arylalkyl”, “arylalkoxy”, or “aryloxyalkyl”, refers to a monocyclic,bicyclic or tricyclic, carbon ring system, that includes fused rings,wherein at least one ring in the system is aromatic. The term “aryl” maybe used interchangeably with the term “aryl ring”. In one embodiment,aryl includes groups having 6-20 carbon atoms (C₆-C₂₀ aryl). In anotherembodiment, aryl includes groups having 6-10 carbon atoms (C₆-C₁₀ aryl).Examples of aryl groups include phenyl, naphthyl, anthracyl, biphenyl,phenanthrenyl, naphthacenyl, 1,2,3,4-tetrahydronaphthalenyl, 1H-indenyl,2,3-dihydro-1H-indenyl, and the like, which may be substituted orindependently substituted by one or more substituents described herein.A particular aryl is phenyl. In another embodiment aryl includes an arylring fused to one or more carbocyclic rings, such as indanyl,dihydrophenanthryl, or tetrahydronaphthyl, and the like, where theradical or point of attachment is on an aromatic ring.

The term “heteroaryl” used alone or as part of a larger moiety, e.g.,“heteroarylalkyl”, or “heteroarylalkoxy”, refers to a monocyclic,bicyclic or tricyclic ring system having 5 to 14 ring atoms, wherein atleast one ring is aromatic and contains at least one heteroatom. In oneembodiment, heteroaryl includes 4-6 membered monocyclic aromatic groupswhere one or more ring atoms is nitrogen, sulfur or oxygen that isindependently optionally substituted. In another embodiment, heteroarylincludes 5-6 membered monocyclic aromatic groups where one or more ringatoms is nitrogen, sulfur or oxygen that is independently optionallysubstituted. In some embodiments, the heteroaryl group is a C₁-C₂₀heteroaryl group, where the heteroaryl ring contains 1-20 carbon atomsand the remaining ring atoms include one or more nitrogen, sulfur, oroxygen atoms. Example heteroaryl groups include thienyl, furyl,imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl,oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl,tetrazinyl, tetrazolo[1,5-b]pyridazinyl, imidazol[1,2-a]pyrimidinyl,purinyl, benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl,benzotriazolyl, benzoimidazolyl, indolyl, 1,3-thiazol-2-yl,1,3,4-triazol-5-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol-5-yl,1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-5-yl, 1H-tetrazol-5-yl,1,2,3-triazol-5-yl, pyrid-2-yl N-oxide, and pyrazolo[4,3-c]pyridinyl.The terms “heteroaryl” also includes groups in which a heteroaryl isfused to one or more aryl, carbocyclyl, or heterocyclyl rings, where theradical or point of attachment is on the heteroaryl ring. Nonlimitingexamples include indolyl, isoindolyl, benzothienyl, benzofuranyl,dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl,isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, andpyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl group may be mono-, bi-or tri-cyclic.

As used herein, the term “heterocyclyl” or “heterocycle” refers to a“carbocyclyl” as defined herein, wherein one or more (e.g. 1, 2, 3, or4) carbon atoms have been replaced with a heteroatom (e.g. O, N, or S).In some embodiments, a heterocyclyl or heterocycle refers to a saturatedring system, such as a 3 to 12 membered saturated heterocyclyl ringsystem. In some embodiments, a heterocyclyl or heterocycle refers to aheteroaryl ring system, such as a 5 to 14 membered heteroaryl ringsystem. A heterocyclyl or heterocycle can optionally be substituted withone or more substituents independently selected from those definedherein.

In one example, heterocyclyl or heterocycle includes 3-12 ring atoms andincludes monocycles, bicycles, tricycles and spiro ring systems, whereinthe ring atoms are carbon, and one to five ring atoms is a heteroatomselected from nitrogen, sulfur or oxygen, which is independentlyoptionally substituted by one or more groups. In one example,heterocyclyl or heterocycle includes 1 to 4 heteroatoms. In anotherexample, heterocyclyl or heterocycle includes 3- to 7-memberedmonocycles having one or more heteroatoms selected from nitrogen, sulfuror oxygen. In another example, heterocyclyl or heterocycle includes 4-to 6-membered monocycles having one or more heteroatoms selected fromnitrogen, sulfur or oxygen. In another example, heterocyclyl orheterocycle includes 3-membered monocycles. In another example,heterocyclyl or heterocycle includes 4-membered monocycles. In anotherexample, heterocyclyl or heterocycle includes 5-6 membered monocycles.In one example, the heterocyclyl or heterocycle group includes 0 to 3double bonds. Any nitrogen or sulfur heteroatom may optionally beoxidized (e.g. NO, SO, SO₂), and any nitrogen heteroatom may optionallybe quaternized (e.g. [NR₄]⁺Cl⁻, [NR₄]⁺OH⁻). Example heterocyclyls orheterocycles include oxiranyl, aziridinyl, thiiranyl, azetidinyl,oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl,dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl,tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl,tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl,oxazinanyl, thiazinanyl, thioxanyl, homopiperazinyl, homopiperidinyl,azepanyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl,1,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl,tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl,1,1-dioxoisothiazolidinonyl, oxazolidinonyl, imidazolidinonyl,4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzoimidazolyl,4,5,6,7-tetrahydrobenzo[d]imidazolyl,1,6-dihydroimidazol[4,5-d]pyrrolo[2,3-b]pyridinyl, thiazinyl, oxazinyl,thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl,thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl,dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl,3-pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl,pyrimidinonyl, pyrimidindionyl, pyrimidin-2,4-dionyl, piperazinonyl,piperazindionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl,3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl,3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl,azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl,8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl,8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane,azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl,1-azaspiro[4.5]decan-2-only, azaspiro[5.5]undecanyl, tetrahydroindolyl,octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl,1,1-dioxohexahydrothiopyranyl. Examples of 5-membered heterocyclyls orheterocycles containing a sulfur or oxygen atom and one to threenitrogen atoms are thiazolyl, including thiazol-2-yl and thiazol-2-ylN-oxide, thiadiazolyl, including 1,3,4-thiadiazol-5-yl and1,2,4-thiadiazol-5-yl, oxazolyl, for example oxazol-2-yl, andoxadiazolyl, such as 1,3,4-oxadiazol-5-yl, and 1,2,4-oxadiazol-5-yl.Example 5-membered ring heterocyclyls or heterocycles containing 2 to 4nitrogen atoms include imidazolyl, such as imidazol-2-yl; triazolyl,such as 1,3,4-triazol-5-yl; 1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl, andtetrazolyl, such as 1H-tetrazol-5-yl. Example benzo-fused 5-memberedheterocyclyls or heterocycles are benzoxazol-2-yl, benzthiazol-2-yl andbenzimidazol-2-yl. Example 6-membered heterocyclyls or heterocyclescontain one to three nitrogen atoms and optionally a sulfur or oxygenatom, for example pyridyl, such as pyrid-2-yl, pyrid-3-yl, andpyrid-4-yl; pyrimidyl, such as pyrimid-2-yl and pyrimid-4-yl; triazinyl,such as 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl; pyridazinyl, inparticular pyridazin-3-yl, and pyrazinyl. The pyridine N-oxides andpyridazine N-oxides and the pyridyl, pyrimid-2-yl, pyrimid-4-yl,pyridazinyl and the 1,3,4-triazin-2-yl groups, are other exampleheterocyclyl groups.

The term “heterocyclyl” or “heterocycle” also includes groups in which aheterocyclyl is fused to one or more aryl, carbocyclyl, or heterocyclylrings, where the radical or point of attachment is on the heterocyclylring. Nonlimiting examples include tetrahydroquinolinyl andtetrahydroisoquinolinyl.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond between ring atoms butthe ring moiety is not aromatic.

As used herein, the term “inhibitor” refers to a compound that binds toand inhibits the bromodomain of CBP and/or EP300 with measurableaffinity and activity. In certain embodiments, an inhibitor has an IC₅₀or binding constant of less about 20 μM, less than about 1 μM, less thanabout 500 nM, less than about 100 nM, or less than about 10 nM.

The terms “measurable affinity” and “measurably inhibit,” as usedherein, refer to a measurable reduction in activity (e.g., reduction inrecognition of lysine acetyl recognition of chromatin) of thebromodomain of CBP and/or EP300 between: (i) a sample comprising acompound of formula I or formula II or composition thereof and suchbromodomain, and (ii) an equivalent sample comprising such bromodomain,in the absence of said compound, or composition thereof.

“Pharmaceutically acceptable salts” include both acid and base additionsalts. It is to be understood that when a compound or Example herein isshown as a specific salt, the corresponding free-base, as well as othersalts of the corresponding free-base (including pharmaceuticallyacceptable salts of the corresponding free-base) are contemplated.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases and which are not biologically or otherwise undesirable, formedwith inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like,and organic acids may be selected from aliphatic, cycloaliphatic,aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes oforganic acids such as formic acid, acetic acid, propionic acid, glycolicacid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid,maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid,citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilicacid, benzoic acid, cinnamic acid, mandelic acid, embonic acid,phenylacetic acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, salicyclic acid and thelike.

“Pharmaceutically acceptable base addition salts” include those derivedfrom inorganic bases such as sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum salts andthe like. Particularly base addition salts are the ammonium, potassium,sodium, calcium and magnesium salts. Salts derived from pharmaceuticallyacceptable organic nontoxic bases includes salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperizine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particular organicnon-toxic bases are isopropylamine, diethylamine, ethanolamine,tromethamine, dicyclohexylamine, choline, and caffeine.

The term “tautomer” or “tautomeric form” refers to structural isomers ofdifferent energies which are interconvertible via a low energy barrier.For example, proton tautomers (also known as prototropic tautomers)include interconversions via migration of a proton, such as keto-enoland imine-enamine isomerizations. Valence tautomers includeinterconversions by reorganization of some of the bonding electrons.

A “solvate” refers to an association or complex of one or more solventmolecules and a compound of the present invention. Examples of solventsinclude water, isopropanol, ethanol, methanol, DMSO, ethyl acetate,acetic acid and ethanolamine. The term “hydrate” refers to the complexwhere the solvent molecule is water.

“Therapeutically effective amount” refers to an amount of a compound ofthe present invention that (i) treats the particular disease, conditionor disorder, (ii) attenuates, ameliorates or eliminates one or moresymptoms of the particular disease, condition, or disorder, or (iii)delays the onset of one or more symptoms of the particular disease,condition or disorder described herein. In the case of cancer, thetherapeutically effective amount of the drug may reduce the number ofcancer cells; reduce the tumor size; inhibit (i.e., slow to some extentand preferably stop) cancer cell infiltration into peripheral organs;inhibit (i.e., slow to some extent and preferably stop) tumormetastasis; inhibit, to some extent, tumor growth; and/or relieve tosome extent one or more of the symptoms associated with the cancer. Forcancer therapy, efficacy can, for example, be measured by assessing thetime to disease progression (TTP) and/or determining the response rate(RR). In the case of immunological disorders, the therapeutic effectiveamount is an amount sufficient to decrease or alleviate an allergicdisorder, the symptoms of an autoimmune and/or inflammatory disease, orthe symptoms of an acute inflammatory reaction (e.g. asthma).

“Treatment” (and variations such as “treat” or “treating”) refers toclinical intervention in an attempt to alter the natural course of theindividual or cell being treated, and can be performed either forprophylaxis or during the course of clinical pathology. Desirableeffects of treatment include one or more of preventing recurrence ofdisease, alleviation of symptoms, diminishment of any direct or indirectpathological consequences of the disease, stabilized (i.e., notworsening) state of disease, preventing metastasis, decreasing the rateof disease progression, amelioration or palliation of the disease state,prolonging survival as compared to expected survival if not receivingtreatment and remission or improved prognosis. In certain embodiments, acompound of formula I or formula II is used to delay development of adisease or disorder or to slow the progression of a disease or disorder.Those individuals in need of treatment include those already with thecondition or disorder as well as those prone to have the condition ordisorder, (for example, through a genetic mutation or abberentexpression of a gene or protein).

“CBP/EP300 bromodomain inhibitor” or “CBP and/or EP300 bromodomaininhibitor” refers to a compound that binds to the CBP bromodomain and/orEP300 bromodomain and inhibits and/or reduces a biological activity ofCBP and/or EP300. In some embodiments, CBP/EP300 bromodomain inhibitorbinds to the CBP and/or EP300 primarily (e.g., solely) through contactsand/or interactions with the CBP bromodomain and/or EP300 bromodomain.In some embodiments, CBP/EP300 bromodomain inhibitor binds to the CBPand/or EP300 through contacts and/or interactions with the CBPbromodomain and/or EP300 bromodomain as well as additional CBP and/orEP300 residues and/or domains. In some embodiments, CBP/EP300bromodomain inhibitor substantially or completely inhibits thebiological activity of the CBP and/or EP300. In some embodiments, thebiological activity is binding of the bromodomain of CBP and/or EP300 tochromatin (e.g., histones associated with DNA) and/or another acetylatedprotein. In certain embodiments, the CBP/EP300 bromodomain inhibitorblocks CBP/EP300 activity so as to restore a functional reponse byT-cells (e.g., proliferation, cytokine production, target cell killing)from a dysfunctional state to antigen stimulation. In some embodiments,the CBP/EP300 bromodomain inhibitor binds to and inhibits CBPbromodomain. In some embodiments, the CBP/EP300 bromodomain inhibitorbinds to and inhibits EP300 bromodomain.

As used herein, “a” or “an” means one or more, unless clearly indicatedotherwise. As used herein, “another” means at least a second or more.

Compounds

Compounds of Formula (I)

Another aspect includes a compound of formula (I):

or a salt thereof.

In one aspect for a compound of formula (I), R³ is not:

In one aspect for a compound of formula (Ia):

or a salt thereof.

In one aspect the compound is a compound of formula (Ib):

or a salt thereof,

In one aspect R¹ is —NHR^(b).

In one aspect R^(b) is C₁₋₆alkyl.

In one aspect R¹ is methyl or —NH(CH₃).

In one aspect m is 0.

In one aspect m is 1.

In one aspect R² is —O—R^(t).

In one aspect R² is —OMe.

In one aspect R³ is 3-12 membered carbocycle that is optionallysubstituted with one or more groups R^(u).

In one aspect R³ is phenyl that is optionally substituted with one ormore groups R.

In one aspect R³ is a 3-12 membered heterocycle that is optionallysubstituted with one or more groups R^(u).

In one aspect R³ is a 9-10 membered heterocycle that is optionallysubstituted with one or more groups R^(u).

In one aspect R³ is selected from the group consisting of:

In one aspect the compound is selected from the group consisting of

and salts thereof.

Compounds of Formula (I

Another aspect includes a compound of formula (II):

or a salt thereof.

In one aspect for a compound of formula (II), R⁶ is not:

In one aspect the compound is a compound is of formula (IIa):

or a salt thereof.

In one aspect the compound is a compound is of formula (IIb):

or a salt thereof.

In one aspect the compound is a compound of formula (IIc):

or a salt thereof.

In one aspect the compound is a compound is of formula (IId):

or a salt thereof.

In one aspect the compound is a compound of formula (IIe):

or a salt thereof.

In one aspect the compound is a compound of formula (IIf):

or a salt thereof.

In one aspect the compound is a compound is of formula (IIg):

or a salt thereof.

In one aspect X is N.

In one aspect X is C(R⁷).

In one aspect R⁷ is H.

In one aspect R⁷ is difluoromethyl.

In one aspect the compound is a compound of formula (IIIh):

or a salt thereof.

In one aspect p is 0.

In one aspect p is 1, 2, 3, or 4.

In one aspect R⁶ is a 3-12 membered heterocycle that is optionallysubstituted with one or more groups R.

In one aspect R⁶ is selected from the group consisting of:

that is optionally substituted with one or more groups R^(x).

In one aspect R⁶ is selected from the group consisting of:

In one aspect the compound selected from the group consisting of

and salts thereof.

Uses, Formulations and Administration of Compounds of Formula (I) orFormula (II)

Pharmaceutically Acceptable Compositions

Another aspect includes a pharmaceutical composition comprising acompound of formula (I) or formula (II) or a pharmaceutically acceptablesalt thereof. In one embodiment, the composition further comprises apharmaceutically acceptable carrier, adjuvant, or vehicle. In anotherembodiment, the composition further comprises an amount of the compoundeffective to measurably inhibit a bromodomain of CBP and/or EP300. Incertain embodiments, the composition is formulated for administration toa patient in need thereof.

The term “patient” or “individual” as used herein, refers to an animal,such as a mammal, such as a human. In one embodiment, patient orindividual refers to a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat may be used in the compositions of this invention include, but arenot limited to, ion exchangers, alumina, aluminum stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

Compositions comprising a compound of formula I or formula II or saltthereof may be administered orally, parenterally, by inhalation spray,topically, transdermally, rectally, nasally, buccally, sublingually,vaginally, intraperitoneal, intrapulmonary, intradermal, epidural or viaan implanted reservoir. The term “parenteral” as used herein includessubcutaneous, intravenous, intramuscular, intra-articular,intra-synovial, intrasternal, intrathecal, intrahepatic, intralesionaland intracranial injection or infusion techniques.

In one embodiment, the composition comprising a compound of formula I orformula II or salt thereof is formulated as a solid dosage form for oraladministration. Solid dosage forms for oral administration includecapsules, tablets, pills, powders, and granules. In certain embodiments,the solid oral dosage form comprising a compound of formula (I) orformula (II) or a salt thereof further comprises one or more of (i) aninert, pharmaceutically acceptable excipient or carrier, such as sodiumcitrate or dicalcium phosphate, and (ii) filler or extender such asstarches, lactose, sucrose, glucose, mannitol, or silicic acid, (iii)binders such as carboxymethylcellulose, alginates, gelatin,polyvinylpyrrolidinone, sucrose or acacia, (iv) humectants such asglycerol, (v) disintegrating agent such as agar, calcium carbonate,potato or tapioca starch, alginic acid, certain silicates or sodiumcarbonate, (vi) solution retarding agents such as paraffin, (vii)absorption accelerators such as quaternary ammonium salts, (viii) awetting agent such as cetyl alcohol or glycerol monostearate, (ix)absorbent such as kaolin or bentonite clay, and (x) lubricant such astalc, calcium stearate, magnesium stearate, polyethylene glycols orsodium lauryl sulfate. In certain embodiments, the solid oral dosageform is formulated as capsules, tablets or pills. In certainembodiments, the solid oral dosage form further comprises bufferingagents. In certain embodiments, such compositions for solid oral dosageforms may be formulated as fillers in soft and hard-filled gelatincapsules comprising one or more excipients such as lactose or milksugar, polyethylene glycols and the like.

In certain embodiments, tablets, dragees, capsules, pills and granulesof the compositions comprising a compound of formula I or formula II orsalt thereof optionally comprise coatings or shells such as entericcoatings. They may optionally comprise opacifying agents and can also beof a composition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions includepolymeric substances and waxes, which may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polethylene glycols andthe like.

In another embodiment, a composition comprises micro-encapsulatedcompound of formula (I) or formula (II) or salt thereof, and optionally,further comprises one or more excipients.

In another embodiment, compositions comprise liquid dosage formulationscomprising a compound of formula I or formula II or salt thereof fororal administration, and optionally further comprise one or more ofpharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In certain embodiments, the liquiddosage form optionally, further comprise one or more of an inert diluentsuch as water or other solvent, a solubilizing agent, and an emulsifiersuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols or fatty acid esters ofsorbitan, and mixtures thereof. In certain embodiments, liquid oralcompositions optionally further comprise one or more adjuvant, such as awetting agent, a suspending agent, a sweetening agent, a flavoring agentand a perfuming agent.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In order to prolong the effect of a compound of formula (I) or formula(II), it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

In certain embodiments, the composition for rectal or vaginaladministration are formulated as suppositories which can be prepared bymixing a compound of formula (I) or formula (II) or a salt thereof withsuitable non-irritating excipients or carriers such as cocoa butter,polyethylene glycol or a suppository wax, for example those which aresolid at ambient temperature but liquid at body temperature andtherefore melt in the rectum or vaginal cavity and release the compoundof formula (I) or formula (II).

Example dosage forms for topical or transdermal administration of acompound of formula (I) or formula (II) include ointments, pastes,creams, lotions, gels, powders, solutions, sprays, inhalants or patches.The compound of formula (I) or formula (II) or a salt thereof is admixedunder sterile conditions with a pharmaceutically acceptable carrier, andoptionally preservatives or buffers. Additional formulation examplesinclude an ophthalmic formulation, ear drops, eye drops, transdermalpatches. Transdermal dosage forms can be made by dissolving ordispensing the compound of formula (I) or formula (II) or a salt thereofin medium, for example ethanol or dimethylsulfoxide. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

Nasal aerosol or inhalation formulations of a compound of formula (I) orformula (II) or a salt thereof may be prepared as solutions in saline,employing benzyl alcohol or other suitable preservatives, absorptionpromotors to enhance bioavailability, fluorocarbons, and/or otherconventional solubilizing or dispersing agents.

In certain embodiments, pharmaceutical compositions may be administeredwith or without food. In certain embodiments, pharmaceuticallyacceptable compositions are administered without food. In certainembodiments, pharmaceutically acceptable compositions of this inventionare administered with food.

Specific dosage and treatment regimen for any particular patient willdepend upon a variety of factors, including age, body weight, generalhealth, sex, diet, time of administration, rate of excretion, drugcombination, the judgment of the treating physician, and the severity ofthe particular disease being treated. The amount of a provided compoundof formula I or formula II or salt thereof in the composition will alsodepend upon the particular compound in the composition.

In one embodiment, the therapeutically effective amount of the compoundof the invention administered parenterally per dose will be in the rangeof about 0.01-100 mg/kg, alternatively about 0.1 to 20 mg/kg of patientbody weight per day, with the typical initial range of compound usedbeing 0.3 to 15 mg/kg/day. In another embodiment, oral unit dosageforms, such as tablets and capsules, contain from about 5 to about 100mg of the compound of the invention.

An example tablet oral dosage form comprises about 2 mg, 5 mg, 25 mg, 50mg, 100 mg, 250 mg or 500 mg of a compound of formula (I) or formula(II) or salt thereof, and further comprises about 5-30 mg anhydrouslactose, about 5-40 mg sodium croscarmellose, about 5-30 mgpolyvinylpyrrolidone (PVP) K30 and about 1-10 mg magnesium stearate. Theprocess of formulating the tablet comprises mixing the powderedingredients together and further mixing with a solution of the PVP. Theresulting composition can be dried, granulated, mixed with the magnesiumstearate and compressed to tablet form using conventional equipment. Anexample of an aerosol formulation can be prepared by dissolving about2-500 mg of a compound of formula I or formula II or salt thereof, in asuitable buffer solution, e.g. a phosphate buffer, and adding atonicifier, e.g. a salt such sodium chloride, if desired. The solutionmay be filtered, e.g. using a 0.2 micron filter, to remove impuritiesand contaminants.

Uses of Compounds and Pharmaceutically Acceptable Compositions

Another aspect includes the use of a compound of formula (I) or formula(II) or a salt thereof for the inhibition of a bromodomain (in vitro orin vivo) (e.g., in vitro or in vivo inhibition of the bromodomain ofCBP/EP300).

Another embodiment includes a method for treating a bromodomain-mediateddisorder (e.g., CBP/EP300 bromodomain-mediated disorder) in an animalcomprising administering a compound of formula (I) or formula (II), or apharmaceutically acceptable salt thereof to the animal.CBP/EP300-mediated disorders include, but are not limited to thosedisorders described herein.

Another embodiment includes a method of increasing efficacy of a cancertreatment comprising a cytotoxic agent in an animal comprisingadministering to the animal an effective amount of a compound of formula(I) or formula (II) or a pharmaceutically acceptable salt thereof.

Another embodiment includes a method of extending the duration ofresponse to a cancer therapy in an animal, comprising administering toan animal undergoing the cancer therapy a compound of formula (I) orformula (II) or a pharmaceutically acceptable salt thereof, wherein theduration of response to the cancer therapy when the compound of formula(I) or formula (II) or the pharmaceutically acceptable salt thereof isadministered is extended over the duration of response to the cancertherapy in the absence of the administration of the compound of formula(I) or formula (II) or the pharmaceutically acceptable salt thereof.

Another embodiment includes a method of treating cancer in an individualcomprising administering to the individual (a) a compound of formula (I)or formula (II) or a pharmaceutically acceptable salt thereof, and (b) acytotoxic agent. In one embodiment the cytotoxic agent is selected fromanti-microtubule agents, platinum coordination complexes, alkylatingagents, antibiotic agents, topoisomerase II inhibitors, antimetabolites,topoisomerase I inhibitors, hormones and hormonal analogues, signaltransduction pathway inhibitors, non-receptor tyrosine kinaseangiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents,inhibitors of LDH-A, inhibitors of fatty acid biosynthesis, cell cyclesignaling inhibitors, HDAC inhibitors, proteasome inhibitors, andinhibitors of cancer metabolism. In one embodiment the cytotoxic agentis a taxane. In one embodiment the taxane is paclitaxel or docetaxel. Inone embodiment the cytotoxic agent is a platinum agent. In oneembodiment the cytotoxic agent is an antagonist of EGFR. In oneembodiment the antagonist of EGFR isN-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine or apharmaceutically acceptable salt thereof (e.g., erlotinib). In oneembodiment the cytotoxic agent is a RAF inhibitor. In one embodiment theRAF inhibitor is a BRAF or CRAF inhibitor. In one embodiment the RAFinhibitor is vemurafenib. In one embodiment the cytotoxic agent is aPI3K inhibitor.

In certain embodiments, treatment may be administered after one or moresymptoms have developed. In other embodiments, treatment may beadministered in the absence of symptoms. For example, treatment may beadministered to a susceptible individual prior to the onset of symptoms(e.g., in light of a history of symptoms and/or in light of genetic orother susceptibility factors). Treatment may also be continued aftersymptoms have resolved, for example to prevent or delay theirrecurrence.

In some embodiments, the CBP/EP300 bromodomain inhibitor interferes withthe associating of CBP and/or EP300 with histones, in particularacetylated lysines in histones. In some embodiments, the CBP/EP300bromodomain inhibitor inhibits binding of CBP and/or EP300 to chromatin(e.g., histone associated DNA). In some embodiments, the CBP/EP300bromodomain inhibitor inhibits and/or reduces binding of the CBPbromodomain and/or EP300 bromodomain to chromatin (e.g., histoneassociated DNA). In some embodiments, the CBP/EP300 bromodomaininhibitor does not affect association of other domains of CBP and/orEP300 to chromatin. In some embodiments, CBP/EP300 bromodomain inhibitorbinds to the CBP and/or EP300 primarily (e.g., solely) through contactsand/or interactions with the CBP bromodomain and/or EP300 bromodomain.In some embodiments, CBP/EP300 bromodomain inhibitor binds to the CBPand/or EP300 through contacts and/or interactions with the CBPbromodomain and/or EP300 bromodomain as well as additional CBP and/orEP300 residues and/or domains. Methods of assaying association withchromatin are known in the art and include, but are not limited to,chromatin fractionation, BRET assay (Promega), FRAP assay, ChromatinImmunoprecipitation (ChIP), biophysical binding assay, and/or HistoneAssociation Assay. See, e.g., Das et al., BioTechniques 37:961-969(2004).

In some embodiments, the CBP/EP300 bromodomain inhibitor does not affecteffector function in CD8 cells (i.e., effector function is substantiallythe same in the presence and/or absence of the CBP/EP300 bromodomaininhibitor). In some embodiments, the CBP/EP300 bromodomain inhibitordoes not affect expression levels of perforin, granzyme, and/or EOMES(i.e., expression levels of one or more perforin, granzyme, and/or EOMESare substantially the same in the presence and/or absence of theCBP/EP300 bromodomain inhibitor). In some embodiments, the CBP/EP300bromodomain inhibitor does not affect expression levels of effectorcytokines IFN-γ and/or TNFα (i.e., expression levels of effectorcytokines IFN-7 and/or TNFα are substantially the same in the presenceand/or absence of the CBP/EP300 bromodomain inhibitor). In someembodiments, the CBP/EP300 bromodomain inhibitor enhances naïve T cellresponsiveness to CD3/CD28 stimulation in the presence of Treg cells.

In some embodiments, the CBP/EP300 bromodomain inhibitor does notsubstantially bind to (e.g., does not bind to) the HAT domain of CBPand/or EP300. In some embodiments, the CBP/EP300 bromodomain inhibitordoes not substantially bind to (e.g., does not bind to) the HAT domainof CBP and/or EP300 as identified in Delvecchio et al., Nat. Struct. &Mol. Biol. 20:1040-1046 (2013), which is incorporated by reference inits entirety. In some embodiments, the CBP/EP300 bromodomain inhibitordoes not substantially bind to one or more residues of the amino acidsequence ENKFSAKRLQTTRLGNHLEDRVNKFLRRQNHPEAGEVFVRVVASSDKTVEVKPGMKSRFVDSGEMSESFPYRTKALFAFEEIDGVDVCFFGMHVQEYGSDCPPPNTRRVYISYLDSIHFFRPRCLRTAVYHEILIGYLEYVKKLGYVTGHIWACPPSEGDDYIFHCHPPDQKIPKPKRLQEWYKKMLDKAFAERIIHDYKDIFKQATEDRLTSAKELPYFEGDFWPNVLEESIKELEQEEEERKKEESTAASETTEGSQGDSKNAKKKNNKKTNKNKSSISRANKKKPSMPNVSNDLSQKLYATMEKHKEVFFVIHLHAGPVINTLPPIVDPDPLLSCDLMDGRDAFLTLARDKHWEFSSLRRSKWSTLCMLVELHTQGQD (amino acid residues 1321-1701 of UniProt No. Q92793 (SEQID NO:1)). In some embodiments, the CBP/EP300 bromodomain inhibitor doesnot substantially bind to one or more residues of the amino acidsequence ENKFSAKRLPSTRLGTFLENRVNDFLRRQNHPESGEVTVRVVHASDKTVEVKPGMKARFVDSGEMAESFPYRTKALFAFEEIDGVDLCFFGMHVQEYGSDCPPPNQRRVYISYLDSVHFFRPKCLRTAVYHEILIGYLEYVKKLGYTTGHIWACPPSEGDDYIFHCHPPDQKIPKPKRLQEWYKKMLDKAVSERIVHDYKDIFKQATEDRLTSAKELPYFEGDFWPNVLEESIKELEQEEEERKREENTSNESTDVTKGDSKNAKKKNNKKTSKNKSSLSRGNKKKPGMPNVSNDLSQKLYATMEKHKEVFFVIRLIAGPAANSLPPIVDPDPLIPCDLMDGRDAFLTLARDKHLEFSSLRRAQWSTMCMLVELHTQSQD (amino acid residues 1285-1664 of UniProt No.Q09472 (SEQ ID NO:2)). In some embodiments, the CBP/EP300 bromodomaininhibitor does not inhibit the histone acetyltransferase (HAT) catalyticactivity of CBP and/or EP300.

Compounds that are CBP/EP300 bromodomain inhibitors are expected to haveimproved and/or distinct properties over other compounds, such as “HAT”inhibitor compounds. HAT inhibition is expected to result in a globalreduction in protein acetylation (histone and non-histone), likelyaffecting cell viability in a significant way. In some embodiments,CBP/EP300 bromodomain inhibition preserves the HAT activity of theseproteins while resulting in the reduction of transcriptional activity ofa relatively small subset of target genes.

In some embodiments, provided are methods of enhancing immune functionin an individual having cancer comprising administering an effectiveamount of any CBP/EP300 bromodomain inhibitors disclosed herein. In someembodiments of any of the methods, the CD8 T cells in the individualhave enhanced priming, activation, proliferation, and/or cytolyticactivity relative to prior to the administration of the CBP/EP300bromodomain inhibitor. In some embodiments, the number of CD8 T cells iselevated relative to prior to administration of the CBP/EP300bromodomain inhibitors. In some embodiments, the CD8 T cells havereduced levels of expression of one or more of the following biomarkers:IFNA17, IGFl, FSCN1, SUMO2, CIorf129, EIF2S2, TDGF1, AIDA, CCR4, CD160,MC4R, KRTAP2-2, MTUP, OR4N2, KRTAP4-5, MTIL//MTIL,IL13, LCEID, KIR2DL2,LOC158696, LIF, 1L28A, TAS2R13, CTLA4, and/or FOXP3 relative to prior toadministration of the CBP/EP300 bromodomain inhibitor. In someembodiments, the CD8 T cells have reduced levels of expression of CD160and/or KIR2DL2 relative to prior to administration of the CBP/EP300bromodomain inhibitor.

In some embodiments of the methods of enhancing immune function, theenhanced immune function is characterized by Treg cells in theindividual (e.g., at the tumor site(s)) have reduced levels ofexpression of one or more of the following markers:lL28A, GPR87,ANKRD37, CABLES1, RAPGEF2, TRIM69, MT1L//MT1L, FAM1138, FOXP3, CSF2,OCM2, GLIPRI, FGFBP2, CTLA4, CST7, GOLGA6L1, IFIT3, FAM13A, APOD, AK2,CLDN1, HSD11B1, DNAJC12, PHEX, IL2, FOXD4L3, GNA15, ZBTB32, RDH10,OR52E5, CYP2A6, GZMH, CCL20, ADM, LOC100131541, RNF122, FAM36A, AMY2B,GPR183, MYOF, IL29, AIDA, SPRYI, ENOPHI, ILIRN, SLAMF1, PGM2L1, SSBP3,MMP23B, HISTlH3J, MYO1B, BENDS, SiPR1, CDK6, GPR56, ZC3HIZA, DOKS,DUSPI, CYB5R2, KCNAB2, LAG3, KLF10, GK, SHC4, IL12RB2, CD109, HAVCR2(TIM-3), LTA, FAM40B, HMGCSI, HSPAIA, ZNF705A, CMAH, KIF3A, CHN1,KBTBD8, TNF, MOP-1, RASGRP4, INSIGI, SLAMF7, OR10H4, LPL, HISTIH2BJ,LIF, IGF1, ILl8RAP, OR52N4, OR1D2, CCR4, CXCR5, ILlR1, MICAL2, NRNI,PICALM, B3GNT5, IFI44L, CXCR3, ICOS, IFIT2, NCR3, HSPAIB, CD80, GNG2,C7orf68, GPR171, RPS10P7, IL23A, LOC283174, PLK2, EMP1, FNBPIL, CD226,RBMS3, IL23R, PTGER4, GZMB, F5, and/or HISTIH2BK relative to prior toadministration of CBP/EP300 bromodomain inhibitor. In some embodiments,the Treg cell biomarker is one or more of LAG3, CTLA4, and/or FOXP3. Insome embodiments of the methods of enhancing immune function, theenhanced immune function is characterized by enhanced naive T cellresponsiveness to CD3/CD28 stimulation in the presence of Treg cells. Insome embodiments, the CD8 T cell priming is characterized by increased Tcell proliferation and/or enhanced cytolytic activity in CD8 T cells. Insome embodiments, the CD8 T cell activation is characterizedby anelevated frequency of T-IFN⁺ CD8 T cells. In some embodiments, the CD8 Tcell is an antigen-specific T-cell. In some embodiments, the immuneevasion is inhibited.

In some embodiments, the methods provided herein are useful in treatingconditions where enhanced immunogenicity is desired such as increasingtumor immunogenicity for the treatment of cancer. For example, providedherein are CBP/EP300 bromodomain inhibitors for use to enhance T-cellfunction to upregulate cell-mediated immune responses and for thetreatment of T cell dysfunctional disorders, tumor immunity. In someembodiments, the CBP/EP300 bromodomain inhibitors promote anti-tumorimmunity by inhibiting the suppressive function of regulatory T (Treg)cells and/or relieving T cell exhaustion on chronically stimulated CD8⁺T cells. CBP/EP300 bromodomain inhibitors are further useful in reducingFOXP3 expression during extra-thymic Treg cell differentiation.Continual FOXP3 expression is essential to maintain suppressive activityin Treg cells. In some embodiments, reduced FOXP3 expression throughCBP/EP300 bromodomain inhibition impairs Treg cells suppressive activityand promotes tumor antiimmunity. Treg cells are highly enriched intumors derived from multiple cancer indications, including melanoma,NSCLC, renal, overian, colon, pancreatic, hepatocellular, and breastcancer. In a subset of these indications, increased intratumoral Tregcell densities are associated with poor patient prognosis. Theseindications include NSCLC, ovarian, pancreatic, hepatocellular, andbreat cancer. CBP/EP300 bromodomain inhibitors are predicted to impairintrtumoral Treg cell function in these cancer indications to enhanceeffector T cell activity. In other embodiments, the CBP/EP300bromodomain inhibitors may be used to treat infectious diseases, wheresome pathogens may have evolved to manipulate regulatory T (Treg) cellsto immunosuppress the host to ensure survival, such as in retrovialinfections (e.g., HIV), mycobacterial infections (e.g., tuberculosis),and parasitic infections (e.g., Leishmania and malaria).

In some embodiments, the methods provided herein are useful in treatinga CBP and/or EP300-mediated disorder involving fibrosis. In someembodiments, the CBP and/or EP300-mediated disorder is a fibroticdisease. Certain fibrotic diseases may include, for example, pulmonaryfibrosis, silicosis, cystic fibrosis, renal fibrosis, liver fibrosis,liver cirrhosis, primary sclerosing cholangitis, primary biliarycirrhosis, endomyocardial fibrosis, mediastinal fibrosis, myelofibrosis,retroperitoneal fibrosis, progressive massive fibrosis, nephrogenicsystemic fibrosis, Crohn's disease, keloid, myocardial infarction,systemic sclerosis or arthro fibrosis.

In other embodiments, the CBP and/or EP300-mediated disorder is afibrotic lung disease. Fibrotic lung diseases may include, for example,idiopathic pulmonary fibrosis, fibrotic interstitial lung disease,interstitial pneumonia, fibrotic variant of non-specific interstitialpneumonia, cystic fibrosis, lung fibrosis, chronic obstructive pulmonarylung disease (COPD), or pulmonary arterial hypertension. In certainembodiments, the fibrotic lung disease is idiopathic pulmonary fibrosis.

CBP and/or EP300-mediated Disorders

A “CBP and/or EP300-mediated disorder” is characterized by theparticipation of the bromodomains of CBP and/or EP300 in the inception,manifestation of one or more symptoms or disease markers, severity, orprogression of a disorder. In one embodiment the bromodomain-mediateddisorder is a CBP bromodomain-mediated disorder. In one embodiment thebromodomain-mediated disorder is an EP300 bromodomain-mediated disorder.

CBP and/or EP300 bromodomain-mediated disorders include cancers,including, but not limited to acoustic neuroma, acute leukemia, acutelymphocytic leukemia, acute myelocytic leukemia (monocytic,myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocyticand promyelocytic), acute T-cell leukemia, basal cell carcinoma, bileduct carcinoma, bladder cancer, brain cancer, breast cancer,bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma,choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronicmyelocytic (granulocytic) leukemia, chronic myelogenous leukemia, coloncancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma,diffuse large B-cell lymphoma, dysproliferative changes (dysplasias andmetaplasias), embryonal carcinoma, endometrial cancer,endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia,esophageal cancer, estrogen-receptor positive breast cancer, essentialthrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germcell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chaindisease, hemangioblastoma, hepatoma, hepatocellular cancer, hormoneinsensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lungcancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblasticleukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignancies andhyperproliferative disorders of the bladder, breast, colon, lung,ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies ofT-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma,meningioma, mesothelioma, multiple myeloma, myelogenous leukemia,myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC),non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenicsarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas,papillary carcinoma, pinealoma, polycythemia vera, prostate cancer,rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma,sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small celllung carcinoma, solid tumors (carcinomas and sarcomas), small cell lungcancer, stomach cancer, squamous cell carcinoma, synovioma, sweat glandcarcinoma, thyroid cancer, Waldenstr6m's macroglobulinemia, testiculartumors, uterine cancer and Wilms' tumor.

In certain embodiments, the cancer is lung cancer, breast cancer,pancreatic cancer, colorectal cancer, and/or melanoma. In certainembodiments, the cancer is lung. In certain embodiments, the lung canceris NSCLC. In certain embodiments, the cancer is breast cancer.

In certain embodiments, the cancer is melanoma.

CBP and/or EP300-mediated disorders also include inflammatory diseases,inflammatory conditions, and autoimmune diseases, including, but notlimited to: Addison's disease, acute gout, ankylosing spondylitis,asthma, atherosclerosis, Behcet's disease, bullous skin diseases,chronic obstructive pulmonary disease (COPD), Crohn's disease,dermatitis, eczema, giant cell arteritis, glomerulonephritis, hepatitis,hypophysitis, inflammatory bowel disease, Kawasaki disease, lupusnephritis, multiple sclerosis, myocarditis, myositis, nephritis, organtransplant rejection, osteoarthritis, pancreatitis, pericarditis,Polyarteritis nodosa, pneumonitis, primary biliary cirrhosis, psoriasis,psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosingcholangitis, sepsis, systemic lupus erythematosus, Takayasu's Arteritis,toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis,vitiligo, vasculitis, and Wegener's granulomatosis.

CBP and/or EP300-mediated disorders also include AIDS; chronic kidneydiseases, including, but are not limited to diabetic nephropathy,hypertensive nephropathy, HIV-associated nephropathy,glomerulonephritis, lupus nephritis, IgA nephropathy, focal segmentalglomerulosclerosis, membranous glomerulonephritis, minimal changedisease, polycystic kidney disease and tubular interstitial nephritis;acute kidney injury or disease or condition including, but are notlimited to ischemia-reperfusion induced, cardiac and major surgeryinduced, percutaneous coronary intervention induced, radio-contrastagent induced, sepsis induced, pneumonia induced, and drug toxicityinduced; obesity; dyslipidemia; hypercholesterolemia; Alzheimer'sdisease; metabolic syndrome; hepatic steatosis; type II diabetes;insulin resistance; and diabetic retinopathy.

CBP and/or EP300 inhibitors may also be used to provide malecontraception.

CBP and/or EP300-mediated disorders also include fibrotic diseases.Certain fibrotic diseases may include, for example, pulmonary fibrosis,silicosis, cystic fibrosis, renal fibrosis, liver fibrosis, livercirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis,endomyocardial fibrosis, mediastinal fibrosis, myelofibrosis,retroperitoneal fibrosis, progressive massive fibrosis, nephrogenicsystemic fibrosis, Crohn's disease, keloid, myocardial infarction,systemic sclerosis or arthro fibrosis.

CBP and/or EP300-mediated disorders also include fibrotic lung diseases.Fibrotic lung diseases may include, for example, idiopathic pulmonaryfibrosis, fibrotic interstitial lung disease, interstitial pneumonia,fibrotic variant of non-specific interstitial pneumonia, cysticfibrosis, lung fibrosis, chronic obstructive pulmonary lung disease(COPD), or pulmonary arterial hypertension. In certain embodiments, thefibrotic lung disease is idiopathic pulmonary fibrosis.

Co-Administration of Compounds and Other Agents

The compounds of formula (I) or formula (II) or salts thereof may beemployed alone or in combination with other agents for treatment. Forexample, the second agent of the pharmaceutical combination formulationor dosing regimen may have complementary activities to the compound offormula (I) or formula (II) such that they do not adversely affect eachother. The compounds may be administered together in a unitarypharmaceutical composition or separately. In one embodiment a compoundor a pharmaceutically acceptable salt can be co-administered with acytotoxic agent to treat proliferative diseases and cancer.

The term “co-administering” refers to either simultaneousadministration, or any manner of separate sequential administration, ofa compound of formula (I) or formula (II) or a salt thereof, and afurther active pharmaceutical ingredient or ingredients, includingcytotoxic agents and radiation treatment. If the administration is notsimultaneous, the compounds are administered in a close time proximityto each other. Furthermore, it does not matter if the compounds areadministered in the same dosage form, e.g. one compound may beadministered topically and another compound may be administered orally.

Those additional agents may be administered separately from an inventivecompound-containing composition, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a compound of this invention in a single composition. Ifadministered as part of a multiple dosage regime, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another normally within five hours from one another.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a compound of thepresent invention may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form. Accordingly, the present inventionprovides a single unit dosage form comprising a compound of formula I orformula I, an additional therapeutic agent, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.

The amount of both an inventive compound and additional therapeuticagent (in those compositions which comprise an additional therapeuticagent as described above) that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. In certainembodiments, compositions of this invention are formulated such that adosage of between 0.01-100 mg/kg body weight/day of an inventive can beadministered.

Typically, any agent that has activity against a disease or conditionbeing treated may be co-administered. Examples of such agents can befound in Cancer Principles and Practice of Oncology by V. T. Devita andS. Hellman (editors), 6^(th) edition (Feb. 15, 2001), LippincottWilliams & Wilkins Publishers. A person of ordinary skill in the artwould be able to discern which combinations of agents would be usefulbased on the particular characteristics of the drugs and the diseaseinvolved.

In one embodiment, the treatment method includes the co-administrationof a compound of formula (I) or formula (II) or a pharmaceuticallyacceptable salt thereof and at least one cytotoxic agent. The term“cytotoxic agent” as used herein refers to a substance that inhibits orprevents a cellular function and/or causes cell death or destruction.Cytotoxic agents include, but are not limited to, radioactive isotopes(e.g., At²¹¹, I¹³¹, I¹²⁵, Y, Re⁸, Re, Sm⁵³, Bi²², P³², Pb²¹² andradioactive isotopes of Lu); chemotherapeutic agents; growth inhibitoryagents; enzymes and fragments thereof such as nucleolytic enzymes; andtoxins such as small molecule toxins or enzymatically active toxins ofbacterial, fungal, plant or animal origin, including fragments and/orvariants thereof.

Exemplary cytotoxic agents can be selected from anti-microtubule agents,platinum coordination complexes, alkylating agents, antibiotic agents,topoisomerase II inhibitors, antimetabolites, topoisomerase Iinhibitors, hormones and hormonal analogues, signal transduction pathwayinhibitors, non-receptor tyrosine kinase angiogenesis inhibitors,immunotherapeutic agents, proapoptotic agents, inhibitors of LDH-A;inhibitors of fatty acid biosynthesis; cell cycle signaling inhibitors;HDAC inhibitors, proteasome inhibitors; and inhibitors of cancermetabolism.

“Chemotherapeutic agent” includes chemical compounds useful in thetreatment of cancer. Examples of chemotherapeutic agents includeerlotinib (TARCEVA®, Genentech/OSI Pharm.), bortezomib (VELCADE,Millennium Pharm.), disulfiram, epigallocatechin gallate,salinosporamide A, carfilzomib, 17-AAG(geldanamycin), radicicol, lactatedehydrogenase A (LDH-A), fulvestrant (FASLODEX, AstraZeneca), sunitib(SUTENT*, Pfizer/Sugen), letrozole (FEMARA®, Novartis), imatinibmesylate (GLEEVEC®., Novartis), finasunate (VATALANIB, Novartis),oxaliplatin (ELOXATIN*, Sanofi), 5-FU (5-fluorouracil), leucovorin,Rapamycin (Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (TYKERB®, GSK572016,Glaxo Smith Kline), Lonafamib (SCH 66336), sorafenib (NEXAVAR®, BayerLabs), gefitinib (IRESSA®, AstraZeneca), AG1478, alkylating agents suchas thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such asbusulfan, improsulfan and piposulfan; aziridines such as benzodopa,carboquone, meturedopa, and uredopa; ethylenimines and methylamelaminesincluding altretamine, triethylenemelamine, triethylenephosphoramide,triethylenethiophosphoramide and trimethylomelamine; acetogenins(especially bullatacin and bullatacinone); a camptothecin (includingtopotecan and irinotecan); bryostatin; callystatin; CC-1065 (includingits adozelesin, carzelesin and bizelesin synthetic analogs);cryptophycins (particularly cryptophycin 1 and cryptophycin 8);adrenocorticosteroids (including prednisone and prednisolone);cyproterone acetate; 5α-reductases including finasteride anddutasteride); vorinostat, romidepsin, panobinostat, valproic acid,mocetinostat dolastatin; aldesleukin, talc duocarmycin (including thesynthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; asarcodictyin; spongistatin; nitrogen mustards such as chlorambucil,chlomaphazine, chlorophosphamide, estramustine, ifosfamide,mechlorethamine, mechlorethamine oxide hydrochloride, melphalan,novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard;nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine,nimustine, and ranimnustine; antibiotics such as the enediyneantibiotics (e.g., calicheamicin, especially calicheamicin γ1I andcalicheamicin Ω1I (Angew Chem. Intl. Ed. Engl. 1994 33:183-186);dynemicin, including dynemicin A; bisphosphonates, such as clodronate;an esperamicin; as well as neocarzinostatin chromophore and relatedchromoprotein enediyne antibiotic chromophores), aclacinomysins,actinomycin, authramycin, azaserine, bleomycins, cactinomycin,carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin,daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCI(doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin,2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin,idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolicacid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogs such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil;amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids suchas maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamnol;nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone;podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharidecomplex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin;sizofuran; spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; trichothecenes (especially T-2 toxin,verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL(paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE®(Cremophor-free), albumin-engineered nanoparticle formulations ofpaclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), andTAXOTERE® (docetaxel, doxetaxel; Sanofi-Aventis); chloranmbucil; GEMZAR®(gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinumanalogs such as cisplatin and carboplatin; vinblastine; etoposide(VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE®(vinorelbine); novantrone; teniposide; edatrexate; daunomycin;aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; topoisomeraseinhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such asretinoic acid; and pharmaceutically acceptable salts, acids andderivatives of any of the above.

Chemotherapeutic agent also includes (i) anti-hormonal agents that actto regulate or inhibit hormone action on tumors such as anti-estrogensand selective estrogen receptor modulators (SERMs), including, forexample, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene,droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxifene, keoxifene,LYl17018, onapristone, and FARESTON® (toremifine citrate); (ii)aromatase inhibitors that inhibit the enzyme aromatase, which regulatesestrogen production in the adrenal glands, such as, for example,4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate),AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR(vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole;AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide,bicalutamide, leuprolide and goserelin; buserelin, tripterelin,medroxyprogesterone acetate, diethylstilbestrol, premarin,fluoxymesterone, all transretionic acid, fenretinide, as well astroxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) proteinkinase inhibitors; (v) lipid kinase inhibitors; (vi) antisenseoligonucleotides, particularly those which inhibit expression of genesin signaling pathways implicated in aberrant cell proliferation, suchas, for example, PKC-alpha, Ralf and H-Ras; (vii) ribozymes such as VEGFexpression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors;(viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN®LEUVECTIN®, and VAXID®; PROLEUKIN®, rIL-2; a topoisomerase 1 inhibitorsuch as LURTOTECAN; ABARELIX® rmRH; and (ix) pharmaceutically acceptablesalts, acids and derivatives of any of the above.

Chemotherapeutic agent also includes antibodies such as alemtuzumab(Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®,Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®,Genentech/Biogen Idec), pertuzumab (OMNITARG®, 2C4, Genentech),trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), andthe antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth).Additional humanized monoclonal antibodies with therapeutic potential asagents in combination with the compounds of the invention include:apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine,cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab,cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab,felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin,ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab,motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab,numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab,pecfusituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab,reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab,sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan,tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab,tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab,ustekinumab, visilizumab, and the anti-interleukin-12 (ABT-874/J695,Wyeth Research and Abbott Laboratories) which is a recombinantexclusively human-sequence, full-length IgG₁ λ antibody geneticallymodified to recognize interleukin-12 p40 protein.

Chemotherapeutic agent also includes “EGFR inhibitors,” which refers tocompounds that bind to or otherwise interact directly with EGFR andprevent or reduce its signaling activity, and is alternatively referredto as an “EGFR antagonist.” Examples of such agents include antibodiesand small molecules that bind to EGFR. Examples of antibodies which bindto EGFR include MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507),MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see, U.S. Pat. No.4,943,533, Mendelsohn et al.) and variants thereof, such as chimerized225 (C225 or Cetuximab; ERBUTIX*) and reshaped human 225 (H225) (see, WO96/40210, Imclone Systems Inc.); IMC-11F8, a fully human, EGFR-targetedantibody (Imclone); antibodies that bind type II mutant EGFR (U.S. Pat.No. 5,212,290); humanized and chimeric antibodies that bind EGFR asdescribed in U.S. Pat. No. 5,891,996; and human antibodies that bindEGFR, such as ABX-EGF or Panitumumab (see WO98/50433, Abgenix/Amgen);EMD 55900 (Stragliotto et al. Eur. J. Cancer 32A:636-640 (1996));EMD7200 (matuzumab) a humanized EGFR antibody directed against EGFR thatcompetes with both EGF and TGF-alpha for EGFR binding (EMD/Merck); humanEGFR antibody, HuMax-EGFR (GenMab); fully human antibodies known asE1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6. 3 and E7.6.3 and described inU.S. Pat. No. 6,235,883; MDX-447 (Medarex Inc); and mAb 806 or humanizedmAb 806 (Johns et al., J. Biol. Chem. 279(29):30375-30384 (2004)). Theanti-EGFR antibody may be conjugated with a cytotoxic agent, thusgenerating an immunoconjugate (see, e.g., EP659,439A2, Merck PatentGmbH). EGFR antagonists include small molecules such as compoundsdescribed in U.S. Pat. Nos. 5,616,582, 5,457,105, 5,475,001, 5,654,307,5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726,6,713,484, 5,770,599, 6,140,332, 5,866,572, 6,399,602, 6,344,459,6,602,863, 6,391,874, 6,344,455, 5,760,041, 6,002,008, and 5,747,498, aswell as the following PCT publications: WO98/14451, WO98/50038,WO99/09016, and WO99/24037. Particular small molecule EGFR antagonistsinclude OSI-774 (CP-358774, erlotinib, TARCEVA® Genentech/OSIPharmaceuticals); PD 183805 (CI 1033, 2-propenamide,N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-,dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSA@)4-(3′-Chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline,AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline,Zeneca); BIBX-1382(N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine,Boehringer Ingelheim); PKI-166((R)-4-[4-[(1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol);(R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine);CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide);EKB-569(N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide)(Wyeth); AG1478 (Pfizer); AG1571 (SU 5271; Pfizer); dual EGFR/HER2tyrosine kinase inhibitors such as lapatinib (TYKERB@, GSK572016 orN-[3-chloro-4-[(3fluorophenyl)methoxy]phenyl]-6[5[[[2methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine).

Chemotherapeutic agents also include “tyrosine kinase inhibitors”including the EGFR-targeted drugs noted in the preceding paragraph;small molecule HER2 tyrosine kinase inhibitor such as TAK165 availablefrom Takeda; CP-724,714, an oral selective inhibitor of the ErbB2receptor tyrosine kinase (Pfizer and OSI); dual-HER inhibitors such asEKB-569 (available from Wyeth) which preferentially binds EGFR butinhibits both HER2 and EGFR-overexpressing cells; lapatinib (GSK572016;available from Glaxo-SmithKline), an oral HER2 and EGFR tyrosine kinaseinhibitor; PKI-166 (available from Novartis); pan-HER inhibitors such ascanertinib (C₁₋₁₀₃₃; Pharmacia); Raf-1 inhibitors such as antisenseagent ISIS-5132 available from ISIS Pharmaceuticals which inhibit Raf-1signaling; non-HER targeted TK inhibitors such as imatinib mesylate(GLEEVEC@, available from Glaxo SmithKline); multi-targeted tyrosinekinase inhibitors such as sunitinib (SUTENT@, available from Pfizer);VEGF receptor tyrosine kinase inhibitors such as vatalanib(PTK787/ZK222584, available from Novartis/Schering AG); MAPKextracellular regulated kinase I inhibitor C₁₋₁₀₄₀ (available fromPharmacia); quinazolines, such as PD 153035,4-(3-chloroanilino)quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines,such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidines,4-(phenylamino)-7H-pyrrolo[2,3-d] pyrimidines; curcumin (diferuloylmethane, 4,5-bis (4-fluoroanilino)phthalimide); tyrphostines containingnitrothiophene moieties; PD-0183805 (Warner-Lamber); antisense molecules(e.g. those that bind to HER-encoding nucleic acid); quinoxalines (U.S.Pat. No. 5,804,396); tryphostins (U.S. Pat. No. 5,804,396); ZD6474(Astra Zeneca); PTK-787 (Novartis/Schering AG); pan-HER inhibitors suchas CI-1033 (Pfizer); Affinitac (ISIS 3521; Isis/Lilly); imatinibmesylate (GLEEVEC@); PKI 166 (Novartis); GW2016 (Glaxo SmithKline);C₁₋₁₀₃₃ (Pfizer); EKB-569 (Wyeth); Semaxinib (Pfizer); ZD6474(AstraZeneca); PTK-787 (Novartis/Schering AG); INC-1C₁₁ (Imclone),rapamycin (sirolimus, RAPAMUNE@); or as described in any of thefollowing patent publications: U.S. Pat. No. 5,804,396; WO 1999/09016(American Cyanamid); WO 1998/43960 (American Cyanamid); WO 1997/38983(Warner Lambert); WO 1999/06378 (Warner Lambert); WO 1999/06396 (WarnerLambert); WO 1996/30347 (Pfizer, Inc); WO 1996/33978 (Zeneca); WO1996/3397 (Zeneca) and WO 1996/33980 (Zeneca).

Chemotherapeutic agents also include dexamethasone, interferons,colchicine, metoprine, cyclosporine, amphotericin, metronidazole,alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide,asparaginase, BCG live, bevacuzimab, bexarotene, cladribine,clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa,elotinib, filgrastim, histrelin acetate, ibritumomab, interferonalfa-2a, interferon alfa-2b, lenalidomide, levamisole, mesna,methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin,palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim,pemetrexed disodium, plicamycin, porfimer sodium, quinacrine,rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene,tretinoin, ATRA, valrubicin, zoledronate, and zoledronic acid, andpharmaceutically acceptable salts thereof.

Chemotherapeutic agents also include hydrocortisone, hydrocortisoneacetate, cortisone acetate, tixocortol pivalate, triamcinoloneacetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide,desonide, fluocinonide, fluocinolone acetonide, betamethasone,betamethasone sodium phosphate, dexamethasone, dexamethasone sodiumphosphate, fluocortolone, hydrocortisone-17-butyrate,hydrocortisone-17-valerate, aclometasone dipropionate, betamethasonevalerate, betamethasone dipropionate, prednicarbate,clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolonecaproate, fluocortolone pivalate and fluprednidene acetate; immuneselective anti-inflammatory peptides (ImSAIDs) such asphenylalanine-glutamine-glycine (FEG) and its D-isomeric form (feG)(IMULAN BioTherapeutics, LLC); anti-rheumatic drugs such asazathioprine, ciclosporin (cyclosporine A), D-penicillamine, gold salts,hydroxychloroquine, leflunomideminocycline, sulfasalazine, tumornecrosis factor alpha (TNFα) blockers such as etanercept (Enbrel),infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia),golimumab (Simponi), Interleukin 1 (IL-1) blockers such as anakinra(Kineret), T cell costimulation blockers such as abatacept (Orencia),Interleukin 6 (IL-6) blockers such as tocilizumab (ACTEMERA@);Interleukin 13 (IL-13) blockers such as lebrikizumab; Interferon alpha(IFN) blockers such as Rontalizumab; Beta 7 integrin blockers such asrhuMAb Beta7; IgE pathway blockers such as Anti-M1 prime; Secretedhomotrimeric LTa3 and membrane bound heterotrimer LTa1/β2 blockers suchas Anti-lymphotoxin alpha (LTa); radioactive isotopes (e.g., At²¹¹,I¹³¹, I²⁵, Y, Re⁸, Re⁹, Sm¹³, Bi²¹², P³², Pb²¹² and radioactive isotopesof Lu); miscellaneous investigational agents such as thioplatin, PS-341,phenylbutyrate, ET-18-OCH₃, or farnesyl transferase inhibitors(L-739749, L-744832); polyphenols such as quercetin, resveratrol,piceatannol, epigallocatechine gallate, theaflavins, flavanols,procyanidins, betulinic acid and derivatives thereof, autophagyinhibitors such as chloroquine; delta-9-tetrahydrocannabinol(dronabinol, MARINOL@); beta-lapachone; lapachol; colchicines; betulinicacid; acetylcamptothecin, scopolectin, and 9-aminocamptothecin);podophyllotoxin; tegafur (UFTORAL@); bexarotene (TARGRETIN@);bisphosphonates such as clodronate (for example, BONEFOS@ or OSTAC@),etidronate (DIDROCAL@), NE-58095, zoledronic acid/zoledronate (ZOMETA@),alendronate (FOSAMAX@), pamidronate (AREDIA@), tiludronate (SKELID®), orrisedronate (ACTONEL@); and epidermal growth factor receptor (EGF-R);vaccines such as THERATOPE@ vaccine; perifosine, COX-2 inhibitor (e.g.celecoxib or etoricoxib), proteosome inhibitor (e.g. PS341); CC₁₋₇₇₉;tipifarnib (R11577); orafenib, ABT510; Bcl-2 inhibitor such asoblimersen sodium (GENASENSE@); pixantrone; farnesyltransferaseinhibitors such as lonafarnib (SCH 6636, SARASAR™); and pharmaceuticallyacceptable salts, acids or derivatives of any of the above; as well ascombinations of two or more of the above such as CHOP, an abbreviationfor a combined therapy of cyclophosphamide, doxorubicin, vincristine,and prednisolone; and FOLFOX, an abbreviation for a treatment regimenwith oxaliplatin (ELOXATINm) combined with 5-FU and leucovorin.

Chemotherapeutic agents also include non-steroidal anti-inflammatorydrugs with analgesic, antipyretic and anti-inflammatory effects. NSAIDsinclude non-selective inhibitors of the enzyme cyclooxygenase. Specificexamples of NSAIDs include aspirin, propionic acid derivatives such asibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin and naproxen,acetic acid derivatives such as indomethacin, sulindac, etodolac,diclofenac, enolic acid derivatives such as piroxicam, meloxicam,tenoxicam, droxicam, lornoxicam and isoxicam, fenamic acid derivativessuch as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamicacid, and COX-2 inhibitors such as celecoxib, etoricoxib, lumiracoxib,parecoxib, rofecoxib, rofecoxib, and valdecoxib. NSAIDs can be indicatedfor the symptomatic relief of conditions such as rheumatoid arthritis,osteoarthritis, inflammatory arthropathies, ankylosing spondylitis,psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhoea,metastatic bone pain, headache and migraine, postoperative pain,mild-to-moderate pain due to inflammation and tissue injury, pyrexia,ileus, and renal colic.

In certain embodiments, chemotherapeutic agents include, but are notlimited to, doxorubicin, dexamethasone, vincristine, cyclophosphamide,fluorouracil, topotecan, interferons, platinum derivatives, taxanes(e.g., paclitaxel, docetaxel), vinca alkaloids (e.g., vinblastine),anthracyclines (e.g., doxorubicin), epipodophyllotoxins (e.g.,etoposide), cisplatin, an mTOR inhibitor (e.g., a rapamycin),methotrexate, actinomycin D, dolastatin 10, colchicine, trimetrexate,metoprine, cyclosporine, daunorubicin, teniposide, amphotericin,alkylating agents (e.g., chlorambucil), 5-fluorouracil, campthothecin,cisplatin, metronidazole, and imatinib mesylate, among others. In otherembodiments, a compound of the present invention is administered incombination with a biologic agent, such as bevacizumab or panitumumab.

In certain embodiments, compounds of the present invention, or apharmaceutically acceptable composition thereof, are administered incombination with an antiproliferative or chemotherapeutic agent selectedfrom any one or more of abarelix, aldesleukin, alemtuzumab,alitretinoin, allopurinol, altretamine, amifostine, anastrozole, arsenictrioxide, asparaginase, azacitidine, BCG live, bevacuzimab,fluorouracil, bexarotene, bleomycin, bortezomib, busulfan, calusterone,capecitabine, camptothecin, carboplatin, carmustine, cetuximab,chlorambucil, cladribine, clofarabine, cyclophosphamide, cytarabine,dactinomycin, darbepoetin alfa, daunorubicin, denileukin, dexrazoxane,docetaxel, doxorubicin (neutral), doxorubicin hydrochloride,dromostanolone propionate, epirubicin, epoetin alfa, elotinib,estramustine, etoposide phosphate, etoposide, exemestane, filgrastim,floxuridine, fludarabine, fulvestrant, gefitinib, gemcitabine,gemtuzumab, goserelin acetate, histrelin acetate, hydroxyurea,ibritumomab, idarubicin, ifosfamide, imatinib mesylate, interferonalfa-2a, interferon alfa-2b, irinotecan, lenalidomide, letrozole,leucovorin, leuprolide acetate, levamisole, lomustine, megestrolacetate, melphalan, mercaptopurine, 6-MP, mesna, methotrexate,methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone,nelarabine, nofetumomab, oprelvekin, oxaliplatin, paclitaxel,palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pipobroman, plicamycin, porfimersodium, procarbazine, quinacrine, rasburicase, rituximab, sargramostim,sorafenib, streptozocin, sunitinib maleate, talc, tamoxifen,temozolomide, teniposide, VM-26, testolactone, thioguanine, 6-TG,thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin,ATRA, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine,zoledronate, or zoledronic acid.

Chemotherapeutic agents also include treatments for Alzheimer's Diseasesuch as donepezil hydrochloride and rivastigmine; treatments forParkinson's Disease such as L-DOPA/carbidopa, entacapone, ropinrole,pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine;agents for treating multiple sclerosis (MS) such as beta interferon(e.g., Avonex® and Rebif®), glatiramer acetate, and mitoxantrone;treatments for asthma such as albuterol and montelukast sodium; agentsfor treating schizophrenia such as zyprexa, risperdal, seroquel, andhaloperidol; anti-inflammatory agents such as corticosteroids, TNFblockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine;immunomodulatory and immunosuppressive agents such as cyclosporin,tacrolimus, rapamycin, mycophenolate mofetil, interferons,corticosteroids, cyclophophamide, azathioprine, and sulfasalazine;neurotrophic factors such as acetylcholinesterase inhibitors, MAOinhibitors, interferons, anti-convulsants, ion channel blockers,riluzole, and anti-Parkinsonian agents; agents for treatingcardiovascular disease such as beta-blockers, ACE inhibitors, diuretics,nitrates, calcium channel blockers, and statins; agents for treatingliver disease such as corticosteroids, cholestyramine, interferons, andanti-viral agents; agents for treating blood disorders such ascorticosteroids, anti-leukemic agents, and growth factors; and agentsfor treating immunodeficiency disorders such as gamma globulin.

Additionally, chemotherapeutic agents include pharmaceuticallyacceptable salts, acids or derivatives of any of chemotherapeuticagents, described herein, as well as combinations of two or more ofthem.

In another embodiment, provided are methods of using CBP/EP300bromodomain inhibitors to treat and/or delay progression of cancer incombination with a PD-1 axis binding antagonist. Further provided hereinare methods of enhancing immune function in an individual having cancercomprising administering to the individual an effective amount of aCBP/EP300 bromodomain inhibitor and an effective amount of a PD-1 axisbinding antagonist. A PD-1 axis binding antagonist includes a PD-1binding antagonist, a PD-L1 binding antagonist and a PD-L2 bindingantagonist.

The term “PD-1 axis binding antagonist” is a molecule that inhibits theinteraction of a PD-1 axis binding partner with either one or more ofits binding partner, so as to remove T-cell dysfunction resulting fromsignaling on the PD-1 signaling axis—with a result being to restore orenhance T-cell function (e.g., proliferation, cytokine production,target cell killing). As used herein, a PD-1 axis binding antagonistincludes a PD-1 binding antagonist, a PD-L1 binding antagonist and aPD-L2 binding antagonist.

The term “PD-1 binding antagonists” is a molecule that decreases,blocks, inhibits, abrogates or interferes with signal transductionresulting from the interaction of PD-1 with one or more of its bindingpartners, such as PDL1, PDL2. In some embodiments, the PD-1 bindingantagonist is a molecule that inhibits the binding of PD-1 to itsbinding partners. In a specific aspect, the PD-1 binding antagonistinhibits the binding of PD-1 to PDL1 and/or PDL2. For example, PD-1binding antagonists include anti-PD-1 antibodies, antigen bindingfragments thereof, immunoadhesins, fusion proteins, oligopeptides andother molecules that decrease, block, inhibit, abrogate or interferewith signal transduction resulting from the interaction of PD-1 withPDL1 and/or PDL2. In one embodiment, a PD-1 binding antagonist reducesthe negative co-stimulatory signal mediated by or through cell surfaceproteins expressed on T lymphocytes mediated signaling through PD-1 soas render a dysfunctional T-cell less dysfunctional (e.g., enhancingeffector responses to antigen recognition). In some embodiments, thePD-1 binding antagonist is an anti-PD-1 antibody. In a specific aspect,a PD-1 binding antagonist is nivolumab described herein (also known asMDX-1106-04, MDX-1106, ONO-4538, BMS-936558, and OPDIVO). In anotherspecific aspect, a PD-1 binding antagonist is pembrolizumab describedherein (also known as MK-3475, Merck 3475, KEYTRUDA®, and SCH-900475).In another specific aspect, a PD-1 binding antagonist is CT-011described herein (also known as hBAT or hBAT-1). In yet another specificaspect, a PD-1 binding antagonist is AMP-224 (also known as B7-DCIg)described herein.

The term “PDL1 binding antagonists” is a molecule that decreases,blocks, inhibits, abrogates or interferes with signal transductionresulting from the interaction of PDL1 with either one or more of itsbinding partners, such as PD-1, B7-1. In some embodiments, a PDL1binding antagonist is a molecule that inhibits the binding of PDL1 toits binding partners. In a specific aspect, the PDL1 binding antagonistinhibits binding of PDL1 to PD-1 and/or B7-1. In some embodiments, thePDL1 binding antagonists include anti-PDL1 antibodies, antigen bindingfragments thereof, immunoadhesins, fusion proteins, oligopeptides andother molecules that decrease, block, inhibit, abrogate or interferewith signal transduction resulting from the interaction of PDL1 with oneor more of its binding partners, such as PD-1, B7-1. In one embodiment,a PDL1 binding antagonist reduces the negative co-stimulatory signalmediated by or through cell surface proteins expressed on T lymphocytesmediated signaling through PDL1 so as to render a dysfunctional T-cellless dysfunctional (e.g., enhancing effector responses to antigenrecognition). In some embodiments, a PDL1 binding antagonist is ananti-PDL1 antibody. In a specific aspect, an anti-PDL1 antibody isYW243.55.S70 described herein. In another specific aspect, an anti-PDL1antibody is MDX-1105 described herein (also known as BMS-936559). Instill another specific aspect, an anti-PDL1 antibody is MPDL3280Adescribed herein. In still another specific aspect, an anti-PDL1antibody is MEDI4736 described herein.

The term “PDL2 binding antagonists” is a molecule that decreases,blocks, inhibits, abrogates or interferes with signal transductionresulting from the interaction of PD-L2 with either one or more of itsbinding partners, such as PD-1. In some embodiments, a PD-L2 bindingantagonist is a molecule that inhibits the binding of PD-L2 to itsbinding partners. In a specific aspect, the PD-L2 binding antagonistinhibits binding of PD-L2 to PD-1. In some embodiments, the PD-L2antagonists include anti-PD-L2 antibodies, antigen binding fragmentsthereof, immunoadhesins, fusion proteins, oligopeptides and othermolecules that decrease, block, inhibit, abrogate or interfere withsignal transduction resulting from the interaction of PD-L2 with eitherone or more of its binding partners, such as PD-1. In one embodiment, aPD-L2 binding antagonist reduces the negative co-stimulatory signalmediated by or through cell surface proteins expressed on T lymphocytesmediated signaling through PD-L2 so as render a dysfunctional T-cellless dysfunctional (e.g., enhancing effector responses to antigenrecognition). In some embodiments, a PD-L2 binding antagonist is animmunoadhesin.

Alternative names for “PD-1” include CD279 and SLEB2. Alternative namesfor “PD-L1” include B7-H 1, B7-4, CD274, and B7-H. Alternative names for“PD-L2” include B7-DC, Btdc, and CD273. In some embodiments, PD-1,PD-L1, and PD-L2 are human PD-1, PD-L1 and PD-L2. In some embodiments,the PD-1 binding antagonist is a molecule that inhibits the binding ofPD-1 to its ligand binding partners. In a specific aspect the PD-1ligand binding partners are PD-L1 and/or PD-L2. In another embodiment, aPD-L1 binding antagonist is a molecule that inhibits the binding ofPD-L1 to its binding partners. In a specific aspect, PD-L1 bindingpartners are PD-1 and/or B7-1. In another embodiment, the PD-L2 bindingantagonist is a molecule that inhibits the binding of PD-L2 to itsbinding partners. In a specific aspect, a PD-L2 binding partner is PD-1.The antagonist may be an antibody, an antigen binding fragment thereof,an immunoadhesin, a fusion protein, or oligopeptide. In some embodiment,the PD-1 binding antagonist is an anti-PD-1 antibody (e.g., a humanantibody, a humanized antibody, or a chimeric antibody). In someembodiments, the anti-PD-1 antibody is selected from the groupconsisting of MDX-1 106, Merck 3475 (also known as: pembrolizumab,lambrolizumab, or MK-3475), nivolumab (BMS-936558), CT-011, andMPDL3280A. In some embodiments, the PD-1 binding antagonist is animmunoadhesin (e.g., an immunoadhesin comprising an extracellular orPD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (e.g.,an Fc region of an immunoglobulin sequence). In some embodiments, thePD-1 binding antagonist is AMP-224. In some embodiments, the PD-L1binding antagonist is anti-PD-L1 antibody. In some embodiments, theanti-PD-L1 binding antagonist is selected from the group consisting ofYW243.55.S70, MPDL3280A and MDX-1 105. MDX-1 105, also known asBMS-936559, is an anti-PD-L antibody described in WO2007/005874.Antibody YW243.55.S70 (heavy and light chain variable region sequencesshown in SEQ ID Nos. 20 and 21, respectively) is an anti-PD-L describedin WO 2010/077634 A1. MDX-1 106, also known as MDX-1 106-04, ONO-4538 orBMS-936558, is an anti-PD-1 antibody described in WO2006/121168. Merck3745, also known as MK-3475 or SCH-900475, is an anti-PD-1 antibodydescribed in WO2009/114335. CT-011, also known as hBAT or hBAT-1, is ananti-PD-1 antibody described in WO2009/101611. AMP-224, also known asB7-DCIg, is a PD-L2-Fc fusion soluble receptor described inWO2010/027827 and WO2011/066342. In some embodiments, the anti-PD-1antibody is MDX-1 106. Alternative names for “MDX-1106” include MDX-1106-04, ONO-4538, BMS-936558 or Nivolumab. In some embodiments, theanti-PD-1 antibody is Nivolumab (CAS Registry Number: 946414-94-4). Insome embodiments, the cancer is melanoma, NSCLC, and renal cellcarcinoma.

For treating an inflammatory disease or an autoimmune disease, acompound of formula (I) or formula (II) or a pharmaceutically acceptablesalt thereof may be co-administered with methotrexate, tofacitinib,6-mercaptopurine, azathioprine sulphasalazine, mesalazine, olsalazinechloroquinine/hydroxychloroquinine, penicillamine, aurothiomalate(intramuscular and oral), azathioprine, cochicine, corticosteroids(oral, inhaled, and local injection), a beta-2 adrenoreceptor agonist(salbutamol, terbutaline, salmeteral), a xanthine (theophylline,aminophylline), cromoglycate, nedocromil, ketotifen, ipratropium andoxitropium, cyclosporin, FK506, rapamycin, mycophenolate mofetil,leflunomide, an NSAID (e.g. ibuprofen), a corticosteroid (e.g.prednisolone), a phosphodiesterase inhibitor, an adensosine agonist, anantithrombotic agent, a complement inhibitor, an adrenergic agent, anagent that interferes with signalling by proinflammatory cytokines suchas TNF or L-1 (e.g., a NIK, IKK, p38 or MAP kinase inhibitor), an L-1converting enzyme inhibitor, a T-cell signalling inhibitor (e.g. akinase inhibitor), a metalloproteinase inhibitor, sulfasalazine, a6-mercaptopurine, an angiotensin converting enzyme inhibitor, a solublecytokine receptor (e.g. soluble p55 or p75 TNF receptors and thederivatives p75TNFRigG (etanercept) and p55TNFRigG (Lenercept), siL-iRI,siL-lRII, siL-6R), an antiinflammatory cytokine (e.g. IL-4, 1L-1 0,IL-11, IL-13 and TGF), celecoxib, folic acid, hydroxychloroquinesulfate, rofecoxib, etanercept, infliximab, adalimumab, certolizumab,tocilizumab, abatacept, naproxen, valdecoxib, sulfasalazine,methylprednisolone, meloxicam, methylprednisolone acetate, gold sodiumthiomalate, aspirin, triamcinolone acetonide, propoxyphenenapsylate/apap, folate, nabumetone, diclofenac, piroxicam, etodolac,diclofenac sodium, oxaprozin, oxycodone HCl, hydrocodonebitartrate/apap, diclofenac sodium/misoprostol, fentanyl, anakinra,tramadol HCl, salsalate, sulindac, cyanocobalamin/fa/pyridoxine,acetaminophen, alendronate sodium, prednisolone, cortisone,betamethasone, morphine sulfate, lidocaine hydrochloride, indomethacin,glucosamine sulf/chondroitin, amitriptyline HCl, sulfadiazine, oxycodoneHCVacetaminophen, olopatadine HCl misoprostol, naproxen sodium,omeprazole, cyclophosphamide, rituximab, IL-1 TRAP, MRA, CTLA4-IG, L-18BP, anti-IL-12, Anti-ILlS, BIRB-796, SCI0-469, VX-702, AMG-548, VX-740,Roflumilast, IC-485, CDC-801, SiPi agonists (such as FTY720), a PKCfamily inhibitor (e.g. Ruboxistaurin or AEB-071) or Mesopram. In certainembodiments, a compound of formula (I) or formula (II) or apharmaceutically acceptable salt thereof may be co-administered withmethotrexate or leflunomide. In moderate or severe Rheumatoid arthritiscases, a compound of formula (I) or formula (II) or a pharmaceuticallyacceptable salt thereof may be co-administered with cyclosporine andanti-TNF antibodies as noted above. A compound of formula (I) or formula(II) or a pharmaceutically acceptable salt thereof may also beco-administered with: budenoside; epidermal growth factor; acorticosteroid; cyclosporin, sulfasalazine; an aminosalicylate;6-mercaptopurine; azathioprine; metronidazole; a lipoxygenase inhibitor;mesalamine; olsalazine; balsalazide; an antioxidant; a thromboxaneinhibitor; an 1L-1 receptor antagonist; an anti-IL-1 monoclonalantibody; an anti-IL-6 monoclonal antibody; a growth factor; an elastaseinhibitor; a pyridinyl-imidazole compound; an antibody to or antagonistof other human cytokines or growth factors (e.g. TNF, LT, IL-1, IL-2,IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-23, EMAP-IL, GM-CSF, FGF, andPDGF); a cell surface molecule (e.g. CD2, CD3, CD4, CD8, CD25, CD28,CD30, CD40, CD45, CD69, or CD90 or their ligands); methotrexate;cyclosporine; FK506; rapamycin; mycophenolate mofetil; leflunomide; anNSAID (e.g. ibuprofen); a corticosteroid (e.g. prednisolone); aphosphodiesterase inhibitor; an adenosine agonist; an antithromboticagent; a complement inhibitor; an adrenergic agent; an agent thatinterferes with signalling by proinflammatory cytokines such as TNF 5 or1L-1 (e.g. a NIK, IKK, or MAP kinase inhibitor); an 1L-1 convertingenzyme inhibitor; a TNF converting enzyme inhibitor; a T-cell signallinginhibitor such as kinase inhibitors; a metalloproteinase inhibitor;sulfasalazine; azathioprine; a 6-mercaptopurine; an angiotensinconverting enzyme inhibitor; a soluble cytokine receptor (e.g. solublep55 or p75 TNF receptors, siL-1RI, siL-1RII, siL-6R), and anantiinflammatory cytokine (e.g. IL-4, IL-1 0, IL-11, IL-13 or TGF).

For treating Crohn's disease, a compound of formula (I) or formula (II)or a pharmaceutically acceptable salt thereof may be co-administeredwith a TNF antagonist (e.g. an anti-TNF antibody), D2E7 (adalimumab),CA2 (infliximab), CDP 571, a TNFR-Ig construct, (p75TNFRigG(etanercept)), a p55TNFRigG (LENERCEPTrm) inhibitor, or a PDE4inhibitor.

For treating inflammatory bowel disease, a compound of formula (I) orformula (II) or a pharmaceutically acceptable salt thereof may beco-administered with a corticosteroid (e.g. budenoside ordexamethasone); sulfasalazine, 5-aminosalicylic acid; olsalazine; anagent that interferes with synthesis or action of proinflammatorycytokines such as IL-1 (e.g. an IL-1 converting enzyme inhibitor orIL-Ira); a T cell signaling inhibitor (e.g. a tyrosine kinaseinhibitor); 6-mercaptopurine; IL-11; mesalamine; prednisone;azathioprine; mercaptopurine; infliximab; methylprednisolone sodiumsuccinate; diphenoxylate/atrop sulfate; loperamide hydrochloride;methotrexate; omeprazole; folate; ciprofloxacin/dextrose-water;hydrocodone bitartrate/apap; tetracycline hydrochloride; fluocinonide;metronidazole; thimerosal/boric acid; cholestyramine/sucrose;ciprofloxacin hydrochloride; hyoscyamine sulfate; meperidinehydrochloride; midazolam hydrochloride; oxycodone HCl/acetaminophen;promethazine hydrochloride; sodium phosphate;sulfamethoxazole/trimethoprim; celecoxib; polycarbophil; propoxyphenenapsylate; hydrocortisone; multivitamins; balsalazide disodium; codeinephosphate/apap; colesevelam HCl; cyanocobalamin; folic acid;levofloxacin; methylprednisolone; natalizumab or interferon-gamma.

For treating multiple sclerosis, a compound of formula (I) or formula(II) or a pharmaceutically acceptable salt thereof may beco-administered with a corticosteroid; prednisolone; methylprednisolone;azathioprine; cyclophosphamide; cyclosporine; methotrexate;4-aminopyridine; tizanidine; interferon-la (AVONEX®; Biogen);interferon-lb (BETASERON@; Chiron/Berlex); interferon-n3) (InterferonSciences/Fujimoto), interferon-(Alfa Wassermann/J&J), interferon 1A-1F(Serono/Inhale Therapeutics), Peginterferon 2b (Enzon/Schering-Plough),Copolymer 1 (Cop-1; COPAXONE®; Teva Pharmaceutical Industries, Inc.);hyperbaric oxygen; intravenous immunoglobulin; cladribine; an antibodyto or antagonist of other human cytokines or growth factors and theirreceptors (e.g. TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-23,IL-15, IL-16, EMAP-II, GM-CSF, FGF, or PDGF).

For treating AIDS a compound of formula (I) or formula (II) or apharmaceutically acceptable salt therof may be co-administered withantibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD19,CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or theirligands. A compound of formula (I) or formula (II) or a pharmaceuticallyacceptable salt thereof may also be co-administered with methotrexate,cyclosporine, FK506, rapamycin, mycophenolate mofetil, leflunomide, anSlPl agonist, an NSAID (e.g. ibuprofen), a corticosteroid (e.g.prednisolone), a phosphodiesterase inhibitor, an adensosine agonist, anantithrombotic agent, a complement inhibitor, an adrenergic agent, anagent that interferes with signalling by proinflammatory cytokines suchas TNF or IL-1 (e.g., a NIK, IKK, p38 or MAP kinase inhibitor), an IL-1converting enzyme inhibitor, a TACE inhibitor, a T-cell signalinginhibitor (e.g. a kinase inhibitor), a metalloproteinase inhibitor,sulfasalazine, azathioprine, a 6-mercaptopurine, an angiotensinconverting enzyme inhibitor, a soluble cytokine receptor (e.g. solublep55 or p75 TNF receptors, siL-RI, siL-1RII, or siL-6R), or anantiinflammatory cytokine (e.g. IL-4, IL-1 0, IL-13 or TGF).

A compound of formula (I) or formula (II) or a pharmaceuticallyacceptable salt thereof may also be co-administered with agents, such asalemtuzumab, dronabinol, daclizumab, mitoxantrone, xaliprodenhydrochloride, fampridine, glatiramer acetate, natalizumab, sinnabidol,immunokine NNSO3, ABR-215062, AnergiX.MS, chemokine receptorantagonists, BBR-2778, calagualine, CPI-1189, LEM (liposome encapsulatedmitoxantrone), THC.CBD (cannabinoid agonist), MBP-8298, mesopram (PDE4inhibitor), MNA-715, an anti-IL-6 receptor antibody, neurovax,pirfenidone allotrap 1258 (RDP-1258), sTNF-R¹, talampanel,teriflunomide, TGF-beta2, tiplimotide, a VLA-4 antagonist (e.g.TR-14035, VLA4 Ultrahaler, or Antegran-ELAN/Biogen), an interferon gammaantagonist, or an IL-4 agonist.

For treating ankylosing spondylitis a compound of formula (I) or formula(II) or a pharmaceutically acceptable salt thereof may beco-administered with ibuprofen, diclofenac, misoprostol, naproxen,meloxicam, indomethacin, diclofenac, celecoxib, rofecoxib,sulfasalazine, methotrexate, azathioprine, minocyclin, prednisone, ananti-TNF antibody, D2E7 (HUMIRA@), CA2 (infliximab), CDP 571, a TNFR-Igconstruct, (p75TNFRigG (ENBREL@), or p55TNFRigG (LENERCEPT@).

For treating asthma a compound of formula (I) or formula (II) or apharmaceutically acceptable salt thereof may be co-administered withalbuterol, salmeterol/fluticasone, montelukast sodium, fluticasonepropionate, budesonide, prednisone, salmeterol xinafoate, levalbuterolHCl, albuterol sulfate/ipratropium, prednisolone sodium phosphate,triamcinolone acetonide, beclomethasone dipropionate, ipratropiumbromide, azithromycin, pirbuterol acetate, prednisolone, theophyllineanhydrous, methylprednisolone sodium succinate, clarithromycin,zafirlukast, formoterol fumarate, influenza virus vaccine, amoxicillintrihydrate, flunisolide, cromolyn sodium, fexofenadine hydrochloride,flunisolide/menthol, amoxicillin/clavulanate, levofloxacin, guaifenesin,dexamethasone sodium phosphate, moxifloxacin HCl, doxycycline hyclate,guaifenesin/d-methorphan, p-ephedrine/cod/-chlorphenir, gatifloxacin,cetirizine hydrochloride, mometasone furoate, salmeterol xinafoate,benzonatate, cephalexin, pe/hydrocodone/chlorphenir, cetirizineHCl/pseudoephed, phenylephrine/cod/promethazine, codeine/promethazine,cefprozil, dexamethasone, guaifenesin/pseudoephedrine,chlorpheniramine/hydrocodone, nedocromil sodium, terbutaline sulfate,epinephrine, methylprednisolone, an anti-IL-13 antibody, ormetaproterenol sulfate.

For treating COPD a compound of formula (I) or formula (II) or apharmaceutically acceptable salt thereof may be co-administered withalbuterol sulfate/ipratropium, ipratropium bromide,salmeterol/fluticasone, albuterol, salmeterol xinafoate, fluticasonepropionate, prednisone, theophylline anhydrous, methylprednisolonesodium succinate, montelukast sodium, budesonide, formoterol fumarate,triamcinolone acetonide, levofloxacin, guaifenesin, azithromycin,beclomethasone dipropionate, levalbuterol HCl, flunisolide, ceftriaxonesodium, amoxicillin trihydrate, gatifloxacin, zafirlukast,amoxicillin/clavulanate, flunisolide/menthol,chlorpheniramine/hydrocodone, metaproterenol sulfate,methylprednisolone, mometasone furoate, p-ephedrine/cod/chlorphenir,pirbuterol acetate, p-ephedrine/loratadine, terbutaline sulfate,tiotropium bromide, (R,R)-formoterol, TgAAT, cilomilast, or roflumilast.

For treating psoriasis, a compound of formula (I) or formula (II) or apharmaceutically acceptable salt thereof may be co-administered withcalcipotriene, clobetasol propionate, triamcinolone acetonide,halobetasol propionate, tazarotene, methotrexate, fluocinonide,betamethasone diprop augmented, fluocinolone acetonide, acitretin, tarshampoo, betamethasone valerate, mometasone furoate, ketoconazole,pramoxine/fluocinolone, hydrocortisone valerate, flurandrenolide, urea,betamethasone, clobetasol propionate/emoll, fluticasone propionate,azithromycin, hydrocortisone, moisturizing formula, folic acid,desonide, pimecrolimus, coal tar, diflorasone diacetate, etanerceptfolate, lactic acid, methoxsalen, he/bismuth subgal/znox/resor,methylprednisolone acetate, prednisone, sunscreen, halcinonide,salicylic acid, anthralin, clocortolone pivalate, coal extract, coaltar/salicylic acid, coal tar/salicylic acid/sulfur, desoximetasone,diazepam, emollient, fluocinonide/emollient, mineral oil/castor oil/nalact, mineral oil/peanut oil, petroleum/isopropyl myristate, psoralen,salicylic acid, soap/tribromsalan, thimerosal/boric acid, celecoxib,infliximab, cyclosporine, alefacept, efalizumab, tacrolimus,pimecrolimus, PUVA, UVB, sulfasalazine, ABT-874 or ustekinamab.

For treating psoriatic arthritis, a compound of formula (I) or formula(II) or a pharmaceutically acceptable salt thereof may beco-administered with methotrexate, etanercept, rofecoxib, celecoxib,folic acid, sulfasalazine, naproxen, leflunomide, methylprednisoloneacetate, indomethacin, hydroxychloroquine sulfate, prednisone, sulindac,betamethasone diprop augmented, infliximab, methotrexate, folate,triamcinolone acetonide, diclofenac, dimethylsulfoxide, piroxicam,diclofenac sodium, ketoprofen, meloxicam, methylprednisolone,nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenacsodium/misoprostol, fluocinonide, glucosamine sulfate, gold sodiumthiomalate, hydrocodone bitartrate/apap, ibuprofen, risedronate sodium,sulfadiazine, thioguanine, valdecoxib, alefacept, D2E7 (adalimumab), orefalizumab.

For treating lupus, a compound of formula (I) or formula (II) or apharmaceutically acceptable salt thereof may be co-administered with anNSAID (e.g. diclofenac, naproxen, ibuprofen, piroxicam, orindomethacin); a COX2 inhibitor (e.g. celecoxib, rofecoxib, orvaldecoxib); an anti-malarial (e.g. hydroxychloroquine); a steroid (e.g.prednisone, prednisolone, budenoside, or dexamethasone); a cytotoxic(e.g. azathioprine, cyclophosphamide, mycophenolate mofetil, ormethotrexate); an inhibitor of PDE4, or a purine synthesis inhibitor(e.g. Cellcept®). For example, a compound of formula (I) or formula (II)or a pharmaceutically acceptable salt thereof may be co-administeredwith sulfasalazine, 5-aminosalicylic acid, olsalazine, Imuran®, an agentthat interferes with the synthesis, production, or action of aproinflammatory cytokine (e.g. IL-l), or a caspase inhibitor (e.g. a I-lconverting enzyme inhibitor or IL-lra).

A compound of formula (I) or formula (II) or a pharmaceuticallyacceptable salt thereof may also be co-administered with a T cellsignaling inhibitor (e.g. a tyrosine kinase inhibitor), or a moleculethat targets T cell activation (e.g. CTLA-4-IgG, an anti-B7 familyantibody, or an anti-PD-1 family antibody).

A compound of formula (I) or formula (II) or a pharmaceuticallyacceptable salt thereof can also be co-administered with an IL-11antibody, an anti-cytokine antibody (e.g. fonotolizumab (anti-IFNgantibody)), or an anti-receptor receptor antibodies (e.g. an anti-IL-6receptor antibody or an antibody to a B-cell surface molecule).

A compound of formula (I) or formula (II) or a pharmaceuticallyacceptable salt thereof can also be co-administered with UP 394(abetimus), an agent that depletes or inactivates B-cells (e.g.Rituximab (anti-CD20 antibody) or lymphostat-B (anti-BlyS antibody)), aTNF antagonist (e.g. an anti-TNF antibody), D2E7 (adalimumab), CA2(infliximab), CDP 571, a TNFR-Ig construct, (p75TNFRigG (etanercept), orp55TNFRigG (LENERCEPT^(T)M).

A compound of formula (I) or formula (II) or a pharmaceuticallyacceptable salt thereof can also be co-administered with one or moreagents used in the prevention or treatment of AIDS: an HIV reversetranscriptase inhibitor, an HIV protease inhibitor, an immunomodulator,or another retroviral drug. Examples of reverse transcriptase inhibitorsinclude, but are not limited to, abacavir, adefovir, didanosine,dipivoxil delavirdine, efavirenz, emtricitabine, lamivudine, nevirapine,rilpivirine, stavudine, tenofovir, zalcitabine, and zidovudine. Examplesof protease inhibitors include, but are not limited to, amprenavir,atazanavir, darunavir, indinavir, fosamprenavir, lopinavir, nelfinavir,ritonavir, saquinavir, and tipranavir. Examples of other retroviraldrugs include, but are not limited to, elvitegravir, enfuvirtide,maraviroc and raltegravir.

For treating type II diabetes, hepatic steatosis, insulin resistance,metabolic syndrome or a related disorder, a compound of formula (I) orformula (II) or a pharmaceutically acceptable salt thereof may beco-administered with insulin or insulins that have been modified toimprove the duration of action in the body; agents that stimulateinsulin secretion such as acetohexamide, chlorpropamide, glyburide,glimepiride, glipizide, glicazide, glycopyramide, gliquidone,rapaglinide, nataglinide, tolazamide or tolbutamide; agents that areglucagon-like peptide agonists such as exanatide, liraglutide ortaspoglutide; agents that inhibit dipeptidyl-peptidase IV such asvildagliptin, sitagliptin, saxagliptin, linagliptin, allogliptin orseptagliptin; agents that bind to the peroxisome proliferator-activatedreceptor gamma such as rosiglitazone or pioglitazone; agents thatdecrease insulin resistance such as metformin; or agents that reduceglucose absorbance in the small intestine such as acarbose, miglitol orvoglibose.

For treating acute kidney disorders or a chronic kidney disease, acompound of formula (I) or formula (II) or a pharmaceutically acceptablesalt thereof may be co-administered with dopamine, a diuretic (e.g.furosemide), bumetanide, thiazide, mannitol, calcium gluconate, sodiumbicarbonate, albuterol, paricalcitol, doxercalciferol, cinacalcet, orbardoxalone methyl.

The amount of both the compound of formula (I) or formula (II) or saltthereof and additional agent (in those compositions which comprise anadditional therapeutic agent as described above) that may be combinedwith the carrier materials to produce a single dosage form will varydepending upon the host treated and the particular mode ofadministration. In certain embodiments, compositions of this inventionare formulated such that a dosage of between 0.01-100 mg/kg bodyweight/day of an inventive can be administered.

The additional therapeutic agent and the compound of formula (I) orformula (II) may act synergistically. Therefore, the amount ofadditional therapeutic agent in such compositions may be less than thatrequired in a monotherapy utilizing only that therapeutic agent, orthere may be fewer side effects for the patient given that a lower doseis used. In certain embodiments, in such compositions a dosage ofbetween 0.01-1,000 μg/kg body weight/day of the additional therapeuticagent can be administered.

Provided herein are methods of extending the duration of response to acytotoxic agent in an individual with cancer comprising administering tothe individual (a) an effective amount of a compound of formula (I) orformula (II) or a pharmaceutically acceptable salt thereof and (b) aneffective amount of the cytotoxic agent.

In certain embodiments of any of the methods, the cytotoxic agent is atargeted therapy. In certain embodiments, the targeted therapy is one ormore of an EGFR antagonist, RAF inhibitor, and/or PI3K inhibitor.

In certain embodiments of any of the methods, the targeted therapy is anEGFR antagonist. In certain embodiments of any of the methods, the EGFRantagonist isN-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine and/or apharmaceutical acceptable salt thereof. In certain embodiments, the EGFRantagonist isN-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine. Incertain embodiments, the EGFR antagonist isN-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-(5-((2-(methylsulfonyl)ethylamino)methyl)furan-2-yl)quinazolin-4-amine,di4-methylbenzenesulfonateor a pharmaceutically acceptable salt thereof (e.g., lapatinib).

In certain embodiments of any of the methods, targeted therapy is a RAFinhibitor. In certain embodiments, the RAF inhibitor is a BRAFinhibitor. In certain embodiments, the RAF inhibitor is a CRAFinhibitor.

In certain embodiments, the BRAF inhibitor is vemurafenib. In certainembodiments, the RAF inhibitor is3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylamino)phenyl)benzamideor a pharmaceutically acceptable salt thereof (e.g., AZ628 (CAS#878739-06-1)).

In certain embodiments of any of the methods, the targeted therapy is aPI3K inhibitor.

In certain embodiments of any of the methods, the cytotoxic agent ischemotherapy. In certain embodiments of any of the methods, thechemotherapy is a taxane. In certain embodiments, the taxane ispaclitaxel. In certain embodiments, the taxane is docetaxel.

In certain embodiments of any of the methods, the cytotoxic agent is aplatinum agent. In certain embodiments, the platinum agent iscarboplatin. In certain embodiments, the platinum agent is cisplatin. Incertain embodiments of any of the methods, the cytotoxic agent is ataxane and a platinum agent. In certain embodiments, the taxane ispaclitaxel. In certain embodiments, the taxane is docetaxel. In certainembodiments, the platinum agent is carboplatin. In certain embodiments,the platinum agent is cisplatin.

In certain embodiments of any of the methods, the cytotoxic agent is avinca alkyloid. In certain embodiments, the vinca alkyloid isvinorelbine. In certain embodiments of any of the methods, thechemotherapy is a nucleoside analog. In certain embodiments, thenucleoside analog is gemcitabine.

In certain embodiments of any of the methods, the cytotoxic agent isradiotherapy.

In certain embodiments of any of the methods, the compound of formula(I) or formula (II) or a pharmaceutically acceptable salt thereof isconcomitantly administered with the cytotoxic agent (e.g., targetedtherapy, chemotherapy, and/or radiotherapy). In certain embodiments, thecompound of formula (I) or formula (II) or a pharmaceutically acceptablesalt thereof is administered prior to and/or concurrently with thecytotoxic agent (e.g., targeted therapy, chemotherapy, and/orradiotherapy).

EXEMPLIFICATION

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that, although the general methods depict thesynthesis of certain compounds of the present invention, the followinggeneral methods, and other methods known to one of ordinary skill in theart, can be applied to all compounds and subclasses and species of eachof these compounds, as described herein.

Compounds of formula (3), (4) and (5) may be prepared by generalsynthetic methods as shown in Scheme 1.

The bromide (2) can cross-couple with tetrahydroquinoline (1) under apalladium catalyst system such as, but not limited to, Xphospre-catalyst in combination with Xphos ligand or Pd-(ipent-PEPPSI) inthe presence of an inorganic base such as, but not limited to, sodiumtert-butoxide or cesium carbonate in a suitable solvent such as1,4-dioxane at elevated temperature to yield compounds of formula (3).In the case where compounds (3) bear a R₁ functional group equals toOtBu, its subjection to the protic conditions described above, followedby treatment with a base such as, but not limited to, triethylamine(TEA), and urea (6) provides compounds of formula (4). Alternatively,compounds (3) can be submitted to protic conditions followed bytreatment with a base such as, but not limited to, triethylamine (TEA),and acetic anhydride provides compounds of formula (5).

Compounds of formula (10) may be prepared by general synthetic methodsas shown in Scheme 2.

Compounds of formula (10) can be prepared from the bromide (7) upontreatment with aryl, heteroaryl or heterocyclic boronic acids (9) orboronate esters (8) under palladium catalyst conditions such as, but notlimited to, Xphos pre-catalyst in combination with Xphos ligand in thepresence of water and an inorganic base such as, but not limited to,sodium carbonate, potassium carbonate, or potassium phosphate in anorganic solvent such as, but not limited to, 1,4-dioxane at an elevatedtemperature. Alternatively, reaction between bromide (7) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (B₂Pin₂) inthe presence of base such as, but not limited to, potassium acetate orpotassium 2-ethyl heanoate, under palladium catalyst conditions such as,but not limited to,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) or Xphospre-catalyst in combination with Xphos ligand in the presence of anorganic solvent such as, but not limited to, 1,4-dioxane ordimethylformamide, can produce the corresponding boronate ester thatupon treatment with aryl, heteroaryl or heterocyclic halides (11 or 12)under the analogous palladium catalyst conditions can also yieldcompounds of formula (10).

Compounds of formula (16) may be prepared by general synthetic methodsas shown in Scheme 3.

The halide (14 or 15) can cross-couple with amine (13) under a palladiumcatalyst system such as, but not limited to, Xphos pre-catalyst incombination with Xphos ligand or Pd-(ipent-PEPPSI) in the presence of aninorganic base such as, but not limited to, sodium tert-butoxide orcesium carbonate in a suitable solvent such as 1,4-dioxane at elevatedtemperature to yield compounds of formula (16).

Compounds of formula (19) may be prepared by general synthetic methodsas shown in Scheme 4.

Compounds of formula (19) can be prepared from a chloride of formula(17) upon treatment with heteroaryl or heterocyclic boronate esters (18)under palladium catalyst conditions such as, but not limited to, Xphospre-catalyst in combination with Xphos ligand in the presence of waterand an inorganic base such as, but not limited to, sodium carbonate,potassium carbonate, or potassium phosphate in an organic solvent suchas, but not limited to, 1,4-dioxane at an elevated temperature.

Compounds of formula (24) may be prepared by general synthetic methodsas shown in Scheme 5.

The bromide (21) can cross-couple with tetrahydroquinoline (20) under apalladium catalyst system such as, but not limited to, Xphospre-catalyst in combination with Xphos ligand or Pd-(ipent-PEPPSI) inthe presence of an inorganic base such as, but not limited to, sodiumtert-butoxide or cesium carbonate in a suitable solvent such as1,4-dioxane at elevated temperature to yield compounds of formula (22)and/or (23). In cases were compound 22 remained, treatment of the esterwith hydroxide sources such as, but not limited to, lithium hydroxide inthe presence of water and organic solvents such as, but not limited to,methanol and/or tetrahydrofuran yields carboxylic acids of formula (22).Reaction of carboxylic acids (22) with a coupling reagent such as, butnot limited to,1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-]pyridinium3-oxide hexafluorophosphate (HATU), a base such as, but not limited to,TEA or diisopropylethylamine, and methylamine hydrochloride providesamides of formula (24).

Compounds of formula (29) may be prepared by general synthetic methodsas shown in Scheme 6.

The bromide (27) can cross-couple with tetrahydroquinoline (26) under apalladium catalyst system such as, but not limited to, Xphospre-catalyst in combination with Xphos ligand or Pd-(ipent-PEPPSI) inthe presence of an inorganic base such as, but not limited to, sodiumtert-butoxide or cesium carbonate in a suitable solvent such as1,4-dioxane at elevated temperature to yield compounds of formula (28).Treatment of the ester with hydroxide sources such as, but not limitedto, lithium hydroxide in the presence of water and organic solvents suchas, but not limited to, methanol and/or tetrahydrofuran yieldscarboxylic acids. Reaction of this carboxylic acids with a couplingreagent such as, but not limited toN,N,N′,N′-Tetramethyl-O-(benzotriazol-1-yl)uroniumtetrafluoroborate(BT), abase such as, but not limited to, TEA ordiisopropylethylamine, and methylamine hydrochloride provides amides offormula (29).

Compounds of formula (33) may be prepared by general synthetic methodsas shown in Scheme 7.

The halide (31 or 32) can cross-couple with tetrahydroquinoline (30)under a palladium catalyst system such as, but not limited to, Xphospre-catalyst in combination with Xphos ligand or Pd-(ipent-PEPPSI) inthe presence of an inorganic base such as, but not limited to, sodiumtert-butoxide or cesium carbonate in a suitable solvent such as1,4-dioxane at elevated temperature to yield compounds of formula (33).

Compounds of formula (37) may be prepared by general synthetic methodsas shown in Scheme 8.

The halide (35 or 36) can cross-couple with tetrahydroquinoline (34)under a palladium catalyst system such as, but not limited to, Xphospre-catalyst in combination with Xphos ligand or Pd-(ipent-PEPPSI) inthe presence of an inorganic base such as, but not limited to, sodiumtert-butoxide or cesium carbonate in a suitable solvent such as1,4-dioxane at elevated temperature to yield compounds of formula (37).

General procedure for Intermediates A

7-bromo-N-methyl-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxamide

To a solution of 7-bromo-2,3,4,5-tetrahydro-1,4-benzoxazepine (500 mg,2.19 mmol) in DCM (11 mL) was added triethylamine (444 mg, 4.40 mmol)and N-methyl-H-imidazole-1-carboxamide (433 mg, 3.29 mmol). The mixturewas stirred at 100° C. for 12 min using a microwave. The crude mixturewas diluted in DCM (10 mL), filtered through celite and concentrated invacuo. The crude residue was purified by silica gel chromatography(iPrOAc/MeOH=97:3) to afford the title compound (Intermediate A, 388 mg,62%) as a white solid. 1H NMR (400 MHz, CDCl₃) δ 7.37-7.28 (m, 2H), 6.91(d, J=8.4 Hz, 1H), 4.40 (s, 2H), 4.35 (s, 1H), 4.12-4.05 (m, 2H),3.85-3.78 (m, 2H), 2.79 (d, J=4.6 Hz, 3H). LCMS M/Z (M+H) 285.

General procedure for Intermediates B

Step 1 N-methyl-1,2,3,5-tetrahydro-1,4-benzodiazepine-4-carboxamide

To a solution of 2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (1.00 g, 6.75mmol) in DCM (34 mL) was added triethylamine (683 mg, 6.75 mmol) andN-methyl-H-imidazole-1-carboxamide (801 mg, 6.08 mmol). The mixture wasstirred at room temperature for 16 h. The crude mixture was diluted inDCM (20 mL), filtered through celite and concentrated in vacuo. Thecrude residue was purified by silica gel chromatography(iPrOAc/MeOH=96:4) to afford the title compound (990 mg, 72%) as a whitesolid. ¹H NMR (400 MHz, CDCl₃, 15/17 H) δ 7.19-7.06 (m, 2H), 6.86 (td,J=7.4, 1.2 Hz, 1H), 6.76 (dd, J=8.0, 1.1 Hz, 1H), 4.35 (s, 2H), 3.97 (s,1H), 3.75-3.67 (m, 2H), 3.23-3.15 (m, 2H), 2.75 (d, J=4.7 Hz, 3H). LCMSM/Z (M+H) 206.

Step 27-bromo-N-methyl-1,2,3,5-tetrahydro-1,4-benzodiazepine-4-carboxamide

To a solution ofN-methyl-1,2,3,5-tetrahydro-1,4-benzodiazepine-4-carboxamide (300 mg,1.46 mmol) in DMF (2.9 mL) was added N-bromosuccinimide (273 mg, 1.53mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min.Then, the reaction mixture was quenched with sat. aq. NaHCO₃ (50 mL) andthe mixture was extracted with DCM (50 mL×3). The combined organiclayers were dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The crude residue was purified by silica gel chromatography(iPrOAc/MeOH=97:3) to afford the title compound (Intermediate B, 225 mg,54%) as an off-white solid. H NMR (400 MHz, CDCl₃) δ 7.34-7.25 (m, 1H),7.19 (dd, J=8.3, 2.3 Hz, 1H), 6.62 (d, J=8.5 Hz, 1H), 4.33 (s, 2H), 4.30(s, 1H), 3.97 (s, 1H), 3.71-3.64 (m, 2H), 3.19 (dt, J=5.1, 3.2 Hz, 2H),2.78 (d, J=4.7 Hz, 3H). LCMS M/Z (M+H) 284.

General procedure for Intermediates C

Step 1 quinoline-7-carbaldehyde

To a solution of 7-methylquinoline (27.0 g, 189 mmol) at 160° C. wasadded SeO2 (21.0 g, 189 mmol) portionwise over 5 min. The mixture wasstirred at 160° C. for 8 h. After cooling the reaction to roomtemperature, DCM (400 mL) was added and the mixture was filtered throughcelite. The organic layer was concentrated in vacuo. The crude residuewas purified by silica gel chromatography (petroleum ether/EtOAc=10:1)to give the title compound (14.0 g, 47%) as yellow oil. ¹H NMR (400 MHz,CDCl₃) δ 10.23 (s, 1H), 9.03 (d, J=2.8 Hz, 1H), 8.56 (s, 1H), 8.22 (d,J=8.4 Hz, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.55-7.52(m, 1H).

Step 2 7-(difluoromethyl)quinoline

To a solution of 7-(difluoromethyl)quinoline (14.0 g, 89.2 mmol) in DCM(150 mL) 0° C. was added diethylaminosulfurtrifluoride (65.0 g, 446mmol) dropwise over 20 min. The mixture was stirred at room temperaturefor 16 h. The mixture was poured into sat. aq. NaHCO₃ (1 L) at 0° C. andextracted with DCM (200 mL×2). The combined organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The cruderesidue was purified by silica gel chromatography (petroleumether/EtOAc=5:1) to give the title compound (13.0 g, 81%) as yellow oil.¹H NMR (400 MHz, CDCl₃) δ 8.92 (d, J=2.8 Hz, 1H), 8.15 (d, J=8.4 Hz,2H), 7.86 (d, J=8.4 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.44-7.41 (m, 1H),6.78 (t, J=56.0 Hz, 1H).

Step 3 7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline

To a solution of 7-(difluoromethyl)quinoline (13.0 g, 72.6 mmol) andNaBH₃CN (23.0 g, 363 mmol) in MeOH (150 mL) at 0° C. was added borontrifluoride diethyl etherate (17.9 mL, 145 mmol) dropwise over 20 min.The mixture was heated to 90° C. for 24 h. After cooling the reaction toroom temperature, the mixture was poured into sat. aq. NaHCO₃ (1 L) at0° C. and extracted with DCM (200 mL×2). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated in vacuo. The cruderesidue was purified by silica gel chromatography (petroleumether/EtOAc=20:1) to give the title compound (8.0 g, 56%) as brown oil.¹H NMR (400 MHz, CDCl₃) δ 7.00 (d, J=7.2 Hz, 1H), 6.71 (d, J=8.0 Hz,1H), 6.59 (s, 1H), 6.50 (t, J=56.8 Hz, 1H), 3.33 (t, J=5.6 Hz, 2H), 2.79(t, J=6.4 Hz, 2H), 1.98-1.92 (m, 2H).

Step 4 6-bromo-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline

To a solution of 7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline (7.0 g,38.3 mmol) in DCM (100 mL) at 0° C. was added N-bromosuccinimide (6.9 g,38.3 mmol) portionwise over 20 min. The mixture was stirred at roomtemperature for 16 h. The mixture was poured into water (100 mL) andextracted with DCM (200 mL×2). The combined organic layers were driedover Na₂SO₄, filtered and concentrated in vacuo. The crude residue waspurified by silica gel chromatography (petroleum ether/EtOAc=300:1) togive the title compound (6.0 g, 60%) as light yellow oil. ¹H NMR (400MHz, CDCl₃) δ 7.13 (s, 1H), 6.78 (t, J=55.2 Hz, 1H), 6.72 (s, 1H), 3.31(t, J=5.2 Hz, 2H), 2.74 (t, J=6.0 Hz, 2H), 1.95-1.87 (m, 2H).

Step 57-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline

To a solution of 6-bromo-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline(600 mg, 2.3 mmol) in dioxane (8 mL) and H₂O (2 mL) was added K₂CO₃ (635mg, 4.6 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (169 mg,0.23 mmol) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(478 mg, 2.3 mmol). The mixture was heated to 110° C. for 18 h under anitrogen atmosphere. After cooling the reaction to room temperature, themixture was concentrated in vacuo. The crude residue was purified bysilica gel chromatography (petroleum ether/EtOAc=40:1) to give the titlecompound (Intermediate C, 520 mg, 86%) as yellow oil. ¹H NMR (400 MHz,CDCl₃) δ 7.52 (s, 1H), 7.39 (s, 1H), 6.96 (s, 1H), 6.81 (s, 1H), 6.54(t, J=55.2 Hz, 1H), 4.12-4.01 (m, 1H), 3.95 (s, 3H), 3.35 (t, J=5.2 Hz,2H), 2.79 (t, J=6.0 Hz, 2H), 2.01-1.91 (m, 2H). LCMS M/Z (M+H) 264. LCMSM/Z (M+H) 264.

General procedure for Intermediates D, E and F

Step 1 8-chloro-3-(1-methyl-1H-pyrazol-4-yl)isoquinoline

To a solution of 3-bromo-8-chloroisoquinoline (500 mg, 2.1 mmol) in1,4-dioxane (10 mL) and water (2 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (75 mg, 0.1mmol), Na₂CO₃ (437 mg, 4.1 mmol) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(472 mg, 2.3 mmol). The mixture was heated to 90° C. for 16 h under anitrogen atmosphere. After cooling the reaction to room temperature,EtOAc (30 mL) was added and washed with water (20 mL×2). The organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The crude residue was purified by silica gel chromatography(DCM/MeOH=20:1) to give the title compound (Intermediate D, 430 mg, 85%)as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.49 (s, 1H), 8.37 (s,1H), 8.14 (s, 1H), 8.10 (s, 1H), 7.89-7.86 (m, 1H), 7.72-7.70 (m, 2H),3.92 (s, 3H).

Step 23-(1-methyl-1H-pyrazol-4-yl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline

To a solution of 8-chloro-3-(1-methyl-1H-pyrazol-4-yl)isoquinoline (10.0g, 41.04 mmol) in 1,4-dioxane (220 mL) was added2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (1.96 g, 4.1mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (3.23 g, 4.1 mmol), KOAc (10.1 g, 102.59 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (31.26 g,123.11 mmol). The mixture was heated to 90° C. for 1 h under a nitrogenatmosphere. After cooling to room temperature, EtOAc (400 mL) was addedand washed with water (200 mL×2). The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude residuewas purified by silica gel chromatography (petroleum ether/EtOAc=1:1) togive the title compound (Intermediate E, 11.0 g, 22% purity) as a brownsolid that required no further purification. LCMS M/Z (M+H) 336.

Step 3 (3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)boronic acid

To a solution of3-(1-methyl-H-pyrazol-4-yl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline(10 g, crude) in acetone (50 mL) and water (50 mL) was added NaIO₄ (16.0g, 74.6 mmol) and NH₄OAc (5.7 g, 74.6 mmol). The mixture was stirred atroom temperature for 48 h. The reaction was filtered and concentrated invacuo. EtOAc (100 mL) was added and washed with water (70 mL), brine (70mL). The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (DCM/MeOH=10:1) to give the title compound (IntermediateF, 440 mg, 4%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.64 (s,1H), 8.57-8.51 (m, 2H), 8.31 (s, 1H), 8.06 (s, 1H), 8.01 (s, 1H), 7.87(d, J=8.4 Hz, 1H), 7.78 (d, J=5.6 Hz, 1H), 7.73-7.63 (m, 1H), 3.91 (s,3H).

General procedure for Intermediate G

Step 1 tert-butyl3-bromo-2-oxo-1,5,7,8-tetrahydro-1,6-naphthyridine-6-carboxylate

To a solution of tert-butyl2-oxo-1,5,7,8-tetrahydro-1,6-naphthyridine-6-carboxylate (275 mg, 1.10mmol) in acetic acid (2.2 mL) at 0° C. was added bromine (67.7 μL, 1.32mmol) portionwise. The mixture was stirred at room temperature for 3 h,then concentrated under reduced pressure. The resulting residue wasdissolved in chloroform (4 mL) and water (2.0 mL). To the solution wasadded Boc₂O (312 mg, 1.43 mmol) and K₂CO₃ (304 mg, 2.20 mmol). Themixture was stirred for 14 h at room temperature. The resultingprecipitate was filtered, washed with diethyl ether, and dried underreduced pressure to give the first batch of the title compound. Themother liquor was poured into a separatory funnel, the organic later wasseparated, dried over Na₂SO₄ and concentrated under reduced pressure.The resulting solid was washed with diethyl ether, and then dried underreduced pressure to give the second batch of the title compound (228 mgtotal, 63%) that required no further purification. ¹H NMR (400 MHz,CDCl₃, 16/17 H) δ 7.59 (s, 1H), 4.32 (s, 2H), 3.67 (t, J=5.8 Hz, 2H),2.74 (t, J=5.8 Hz, 2H), 1.48 (s, 9H).

Step 2 tert-butyl3-bromo-1-methyl-2-oxo-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylate

To a solution of tert-butylbromo-2-oxo-1,5,7,8-tetrahydro-1,6-naphthyridine-6-carboxylate (124 mg,0.378 mmol) in DMF (1.5 mL) at 0° C. was added a solution of HMDS inhexane (1.0 M, 0.567 mL, 0.567 mmol). After stirring for 15 min,iodomethane (47.1 μL, 0.756 mmol) was added. After stirring for anadditional 30 min, the reaction mixture was concentrated under reducedpressure. The residue was purified by silica gel chromatography (100%Heptanes to 100% EtOAc gradient) to afford the title compound (87.5 mg,68%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.50 (s, 1H), 4.31 (t, J=1.6 Hz, 2H),3.69 (t, J=5.8 Hz, 2H), 3.57 (s, 3H), 2.69 (t, J=1.7 Hz, 2H), 1.49 (s,9H).

Step 3 6-acetyl-3-bromo-1-methyl-7,8-dihydro-5H-1,6-naphthyridin-2-one

A mixture of tert-butyl3-bromo-1-methyl-2-oxo-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylate(60 mg, 0.175 mmol) and trifluoroacetic acid (0.5 mL) in DCM (4 mL) wasstirred at room temperature for 2 h. The solvent was concentrated underreduced pressure and the crude product was re-dissolved in DCM (4 mL).The solution was cooled to 0° C. before TEA (0.122 mL, 0.874 mmol) andacetic anhydride (33.1 μL, 0.350 mmol) were added dropwise. The reactionmixture was stirred at room temperature for additional 3 h before it wasquenched with water. The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The crude residue waspurified by silica gel chromatography (100% Heptanes to 10% MeOH inEtOAc gradient) to afford the title compound (Intermediate G, 39.8 mg,80%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.52 (d, J=4.6 Hz, 1H),4.53-4.32 (m, 2H), 3.88-3.74 (m, 2H), 3.57 (d, J=1.3 Hz, 3H), 2.82-2.64(m, 2H), 2.17 (d, J=9.4 Hz, 3H).

Example 17-(isoquinolin-1-yl)-N-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxamide

To a solution of7-bromo-N-methyl-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxamide(Intermediate A, 50 mg, 0.18 mmol) and bis(pinacolato)diboron (89 mg,0.35 mmol) in dioxane (0.88 mL) was added KOAc (52 mg, 0.53 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(4.2 mg, 0.0053 mmol) and2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (5.1 mg, 0.010mmol). The mixture was stirred at 80° C. for 16 h under a nitrogenatmosphere. The reaction mixture was cooled to room temperature and1-bromoisoquinoline (25 mg, 0.12 mmol), K₃PO₄.H₂O (71 mg, 0.30 mmol),water (0.3 mL) andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(4.2 mg, 0.0053 mmol) were added. The reaction mixture was stirred at70° C. for 4 h under a nitrogen atmosphere. The reaction mixture wasthen cooled to room temperature and concentrated in vacuo. The cruderesidue was diluted in dichloromethane (5 mL), dried over anhydrousMgSO₄, filtered through celite and concentrated in vaco. The mixtureobtained was purified by reverse phase chromatography (acetonitrile20-6%/0.1% ammonium hydroxide in water) to give the title compound (8.4mg, 14%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.57 (d, J=5.7Hz, 1H), 8.07 (td, J=8.0, 1.1 Hz, 2H), 7.87-7.76 (m, 2H), 7.73 (d, J=2.3Hz, 1H), 7.66 (ddd, J=8.4, 6.9, 1.4 Hz, 1H), 7.52 (dd, J=8.2, 2.3 Hz,1H), 7.14 (d, J=8.2 Hz, 1H), 6.55 (q, J=4.3 Hz, 1H), 4.56 (s, 2H), 4.11(dd, J=5.2, 3.6 Hz, 2H), 3.76 (dd, J=5.2, 3.4 Hz, 2H), 2.55 (d, J=4.3Hz, 3H). LCMS M/Z (M+H) 334.

The following compound was prepared in a similar fashion to Example 1:

Example Compound Name and Structure NMR m/z Example 27-(3-amino-2,6-naphthyridin- Not 350 1-yl)-N-methyl-3,5-dihydro-Determined 2H-1,4-benzoxazepine-4- carboxamide

Example 37-(1,5-dimethylindazol-4-yl)-N-methyl-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxamide

To a solution of7-bromo-N-methyl-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxamide(Intermediate A, 50 mg, 0.18 mmol) and (1,5-dimethylindazol-4-yl)boronicacid (67 mg, 0.35 mmol) in dioxane (1.2 mL) and water (0.4 mL) was addedK₃PO₄.H₂O (103 mg, 0.438 mmol),(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (9.4 mg, 0.010 mmol) and2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (5.1 mg, 0.010mmol). The mixture was stirred at 90° C. for 16 h under a nitrogenatmosphere. The reaction mixture was then cooled to room temperature andconcentrated in vacuo. The crude residue was diluted in dichloromethane(5 mL), dried over anhydrous MgSO₄, filtered through celite andconcentrated in vaco. The mixture obtained was purified by reverse phasechromatography (acetonitrile 20-60%/0.1% ammonium hydroxide in water) togive the title compound (52 mg, 82%) as a white solid. 1H NMR (400 MHz,DMSO-d₆) δ 7.60 (d, J=1.0 Hz, 1H), 7.53 (dd, J=8.5, 1.0 Hz, 1H), 7.49(d, J=2.2 Hz, 1H), 7.34 (d, J=8.6 Hz, 1H), 7.25 (dd, J=8.2, 2.2 Hz, 1H),7.09 (d, J=8.2 Hz, 1H), 6.54 (q, J=4.3 Hz, 1H), 4.51 (s, 2H), 4.11-4.05(m, 2H), 4.04 (s, 3H), 3.78-3.71 (m, 2H), 2.55 (d, J=4.2 Hz, 3H), 2.32(s, 3H). LCMS M/Z (M+H) 351.

The following compounds were prepared in a similar fashion to Example 3:

Compound Name and Example Structure NMR m/z Example 4

¹H NMR (400 MHz, DMSO-d₆) δ 8.94 (d, J = 4.4 Hz, 1H), 8.15-8.07 (m, 1H),7.98-7.90 (m, 1H), 7.85- 7.76 (m, 1H), 7.66-7.57 (m, 2H), 7.45 (d, J =4.4 Hz, 1H), 7.40 (dd, J = 8.2, 2.3 Hz, 1H), 7.16 (d, J = 8.2 Hz, 1H),6.58-6.49 (m, 1H), 4.55 (s, 2H), 4.19-4.04 (m, 2H), 3.82- 3.71 (m, 2H),2.56 (d, J = 4.3 Hz, 3H). 334 Example 5

¹H NMR (400 MHz, DMSO-d₆) δ 8.47-8.42 (m, 1H), 7.78-7.72 (m, 1H),7.61-7.54 (m, 1H), 7.54- 7.49 (m, 1H), 7.37-7.26 (m, 1H), 7.12 (dd, J =6.9, 0.8 Hz, 1H), 7.08 (d, J = 8.2 Hz, 1H), 6.57-6.48 (m, 1H), 4.54 (s,2H), 4.19 (s, 3H), 4.09- 4.02 (m, 2H), 3.80-3.72 (m, 2H), 2.54 (d, J =4.3 Hz, 3H). 337 Example 6

¹H NMR (400 MHz, DMSO-d₆) δ 8.94 (dd, J = 4.1, 1.7 Hz, 1H), 8.28- 8.18(m, 1H), 8.11-7.99 (m, 1H), 7.91-7.75 (m, 1H), 7.60-7.48 (m, 3H),7.38-7.26 (m, 1H), 7.13 (d, J = 8.1 Hz, 1H), 6.58-6.46 (m, 1H),4.59-4.48 (m, 2H), 4.14-4.03 (m, 2H), 3.80-3.73 (m, 2H), 2.55 (d, J =4.3 Hz, 3H). 334 Example 7

¹H NMR (400 MHz, DMSO-d₆) δ 7.40-7.30 (m, 1H), 7.21-7.10 (m, 2H),7.09-7.03 (m, 1H), 7.03- 6.96 (m, 2H), 6.53-6.42 (m, 1H), 4.47 (d, J =1.7 Hz, 2H), 4.09-3.98 (m, 2H), 3.77-3.68 (m, 2H), 2.55- 2.52 (m, 3H),2.29 (s, 3H), 2.19 (s, 3H). 311 Example 8

¹H NMR (400 MHz, DMSO-d₆) δ 8.14 (s, 1H), 7.80-7.75 (m, 1H), 7.48 (d, J= 2.3 Hz, 1H), 7.30 (dd, J = 8.1, 2.3 Hz, 1H), 7.18 (dd, J = 4.6, 0.9Hz, 2H), 7.08 (d, J = 8.1 Hz, 1H), 6.57-6.45 (m, 1H), 4.51 (s, 2H),4.16-4.01 (m, 2H), 3.84- 3.69 (m, 2H), 3.60 (s, 3H), 2.54 (d, J = 4.3Hz, 3H). 337 Example 9

¹H NMR (400 MHz, DMSO-d₆) δ 13.02 (s, 1H), 7.65 (d, J = 1.4 Hz, 1H),7.50 (d, J = 2.3 Hz, 1H), 7.45- 7.39 (m, 1H), 7.32-7.23 (m, 2H), 7.09(d, J = 8.1 Hz, 1H), 6.55 (d, J = 4.5 Hz, 1H), 4.51 (s, 2H), 4.13- 4.04(m, 2H), 3.79-3.71 (m, 2H), 2.55 (d, J = 4.2 Hz, 3H), 2.31 (s, 3H). 337Example 10

¹H NMR (400 MHz, DMSO-d₆) δ 8.14 (d, J = 1.0 Hz, 1H), 7.78 (d, J = 2.3Hz, 1H), 7.65-7.59 (m, 1H), 7.54 (dd, J = 8.2, 2.3 Hz, 1H), 7.48 (dd, J= 8.4, 7.1 Hz, 1H), 7.23 (dd, J = 7.1, 0.8 Hz, 1H), 7.11 (d, J = 8.2 Hz,1H), 6.64-6.52 (m, 1H), 4.55 (s, 2H), 4.09 (s, 3H), 4.08-4.05 (m, 2H),3.80-3.69 (m, 2H), 2.55 (d, J = 4.3 Hz, 3H). 337 Example 11

¹H NMR (400 MHz, DMSO-d₆) δ 9.33 (d, J = 0.8 Hz, 1H), 8.43 (s, 1H),8.26-8.15 (m, 1H), 7.95- 7.86 (m, 1H), 7.84-7.77 (m, 1H), 7.79-7.71 (m,1H), 7.60 (d, J = 2.3 Hz, 1H), 7.38 (dd, J = 8.2, 2.3 Hz, 1H), 7.15 (d,J = 8.1 Hz, 1H), 6.60- 6.47 (m, 1H), 4.54 (s, 2H), 4.14- 4.06 (m, 2H),3.83-3.69 (m, 2H), 2.56 (d, J = 4.3 Hz, 3H). 334 Example 12

¹H NMR (400 MHz, DMSO-d₆) δ 11.28 (s, 1H), 7.62 (dd, J = 2.3, 1.3 Hz,1H), 7.48-7.43 (m, 1H), 7.40- 7.35 (m, 2H), 7.08 (d, J = 8.2 Hz, 1H),7.06-6.98 (m, 1H), 6.55 (d, J = 4.4 Hz, 1H), 6.45-6.33 (m, 1H), 4.52 (s,2H), 4.13-3.99 (m, 2H), 3.79-3.66 (m, 2H), 2.54 (d, J = 4.3 Hz, 3H). 340Example 13

¹H NMR (400 MHz, DMSO-d₆) δ 11.12 (s, 1H), 7.79-7.73 (m, 1H), 7.68 (d, J= 2.4 Hz, 1H), 7.50-7.40 (m, 2H), 7.40-7.31 (m, 2H), 7.01 (d, J = 8.2Hz, 1H), 6.56-6.42 (m, 2H), 4.51 (s, 2H), 4.06-3.97 (m, 2H), 3.77-3.69(m, 2H), 2.54 (d, J = 4.3 Hz, 3H). 322 Example 14

¹H NMR (400 MHz, DMSO-d₆) δ 13.21 (s, 1H), 8.17 (t, J = 1.3 Hz, 1H),7.79 (d, J = 2.3 Hz, 1H), 7.57- 7.50 (m, 2H), 7.46-7.40 (m, 1H), 7.19(dd, J = 7.1, 0.8 Hz, 1H), 7.11 (d, J = 8.2 Hz, 1H), 6.66-6.54 (m, 1H),4.55 (s, 2H), 4.11-4.01 (m, 2H), 3.78-3.69 (m, 2H), 2.55 (d, J = 4.3 Hz,3H). 323 Example 15

¹H NMR (400 MHz, DMSO-d₆, 17/ 18 H) δ 8.18 (s, 1H), 7.81-7.71 (m, 2H),7.52 (dd, J = 8.2, 2.4 Hz, 1H), 7.36 (dd, J = 7.1, 1.0 Hz, 1H), 7.21(dd, J = 8.0, 7.1 Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H), 6.48 (q, J = 4.4Hz, 1H), 4.55 (s, 2H), 4.17-3.99 (m, 2H), 3.83-3.64 (m, 2H), 2.62- 2.48(m, 3H). 323

Example 167-[7-(difluoromethyl)-6-(l-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-N-methyl-1,2,3,5-tetrahydro-1,4-benzodiazepine-4-carboxamide

To a solution of7-bromo-N-methyl-1,2,3,5-tetrahydro-1,4-benzodiazepine-4-carboxamide(Intermediate B, 45 mg, 0.16 mmol) in 2-methyl-2-butanol (0.32 mL) anddioxane (0.40 mL) was addeddichloro[1,3-bis(2,6-Di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)(13mg, 0.016 mmol), t-BuONa (46 mg, 0.48 mmol) and7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline(Intermediate C, 83 mg, 0.32 mmol). The reaction mixture was stirred at90° C. for 16 h under a nitrogen atmosphere. The crude residue wasdiluted in dichloromethane (5 mL), dried over anhydrous MgSO₄, filteredthrough celite and concentrated in vaco. The mixture obtained waspurified by reverse phase chromatography (acetonitrile 20-60%/0.1%formic acid in water) followed by SFC (Pyridyl amide 150030.0 mm I.D, 5m; 20-60% of 0.1% ammonium hydroxide in MeOH/Supercritical CO₂) to givethe title compound (9.2 mg, 12%) as white solid. ¹H NMR (400 MHz,DMSO-d₆,27/28H) δ 7.72 (s, 1H), 7.47 (d, J=0.8 Hz, 1H), 7.18 (d, J=2.5Hz, 1H), 7.06 (s, 1H), 6.96-6.82 (m, 2H), 6.75-6.55 (m, 1H), 6.27 (q,J=4.3 Hz, 1H), 5.59 (t, J=3.5 Hz, 1H), 4.29 (s, 2H), 3.86 (s, 3H),3.55-3.42 (m, 4H), 3.03 (s, 2H), 2.83 (d, J=Hz, 2H), 2.52 (d, J=4.2 Hz,3H), 2.04-1.94 (m, 2H). LCMS M/Z (M+H). 467.

The following compounds were prepared in a similar fashion to Example16:

Compound Name and Example Structure NMR m/z Example 17

¹H NMR (400 MHz, DMSO-d₆) δ 7.72 (s, 1H), 7.47 (t, J = 1.1 Hz, 1H),7.40-7.36 (m, 1H), 7.05 (s, 1H), 6.89-6.57 (m, 1H), 6.42-6.39 (m, 1H),4.42-4.39 (m, 2H), 3.86 (s, 3H), 3.73 (t, J = 5.9 Hz, 2H), 3.48- 3.41(m, 5H), 2.90-2.79 (m, 4H), 2.10-2.06 (m, 3H), 1.97 (t, J = 6.0 Hz, 2H).468 Example 18

¹H NMR (400 MHz, DMSO-d₆, 20/ 23 H) δ 7.72 (d, J = 0.8 Hz, 1H), 7.47 (d,J = 0.8 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 7.14 (d, J = 2.0 Hz, 1H),7.08 (d, J = 1.4 Hz, 1H), 6.98 (dd, J = 8.3, 2.0 Hz, 1H), 6.86-6.55 (m,2H), 3.86 (s, 3H), 3.64-3.56 (m, 2H), 3.35 (s, 3H), 2.95-2.76 (m, 2H),2.10-1.93 (m, 2H). 424 Example 19

¹H NMR (400 MHz, DMSO-d₆) δ 7.75 (d, J = 0.8 Hz, 1H), 7.50 (d, J = 0.8Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.12 (s, 1H), 6.99 (d, J = 2.0 Hz,1H), 6.93-6.60 (m, 3H), 3.86 (s, 3H), 3.68-3.59 (m, 2H), 3.21 (s, 3H),2.91-2.80 (m, 4H), 2.57 (dd, J = 8.6, 6.1 Hz, 2H), 1.99 (p, J = 6.2 Hz,2H). 423 Example 20

¹H NMR (400 MHz, DMSO-d₆) δ 7.75 (d, J = 0.8 Hz, 1H), 7.50 (d, J = 0.8Hz, 1H), 7.35 (d, J = 7.9 Hz, 1H), 7.13 (s, 1H), 6.98-6.59 (m, 4H), 3.87(s, 3H), 3.71-3.55 (m, 2H), 3.11 (s, 3H), 2.85 (t, J = 6.4 Hz, 2H),2.07-1.91 (m, 2H), 1.29 (s, 6H). 437

Example 215-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-3-methyl-1,3-benzothiazol-2-one

Step 1 5-bromo-3H-1,3-benzothiazol-2-one

To a solution of 2-amino-4-bromobenzenethiol (544 mg, 2.67 mmol) inacetic acid (26.7 mL) was added triphosgene (530 mg, 1.79 mmol). Themixture was heated at reflux for 18 h. After cooling to roomtemperature, the solution was partially concentrated under reducedpressure, water was added, and the resulting precipitate was removed viafiltration, and washed with aqueous NaOH (1.0 M). The filtrate wasacidified with HCl (2 N) to pH 2, and placed in a refrigerator for 12 h.The resulting precipitate was filtered, washed with water, and driedunder reduced pressure to give the title compound (94 mg, 15%) as awhile powder that required no further purification. ¹H NMR (400 MHz,DMSO-d₆) δ 12.07 (s, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.30 (d, J=8.0 Hz,1H), 7.24 (s, 1H).

Step 2 5-bromo-3-methyl-1,3-benzothiazol-2-one

To a solution of 5-bromo-3H-1,3-benzothiazol-2-one (94.4 mg, 0.410 mmol)in water (2.1 mL) was added NaOH (16.4 mg, 0.410 mmol) and then dimethylsulfate (62.1 mg, 0.492 mmol). After stirring at room temperature for 3h, the resulting precipitate was filtered, washed with water, and driedunder reduced pressure to give the title compound (89.3 mg, 89%) as awhite powder that required no further purification. ¹H NMR (400 MHz,CDCl₃) δ 7.32-7.29 (m, 2H), 7.20 (dd, J=1.5, 0.6 Hz, 1H), 3.45 (s, 3H).

Step 35-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-3-methyl-1,3-benzothiazol-2-one

To a vial was added7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydroquinoline(Intermediate C, 25.0 mg, 0.0950 mmol),5-bromo-3-methyl-1,3-benzothiazol-2-one (27.8 mg, 0.114 mmol),dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)(11.9 mg, 0.0142 mmol), t-BuONa (18.2 mg, 0.190 mmol) and 1,4-dioxane(0.20 mL). The mixture was sparged with an argon balloon, and thenheated to 120° C. for 16 h under an argon atmosphere. After cooling thereaction to room temperature, DCM (3 mL) was added and the reaction wasfiltered through celite and concentrated under reduced pressure. Thecrude residue was purified by reverse phase preparative HPLC(acetonitrile 30-70%/0.1% ammonium hydroxide in water) to give the titlecompound (9.6 mg, 24%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ7.76 (d, J=0.8 Hz, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.51 (d, J=0.8 Hz, 7.26(d, J=2.1 Hz, 1H), 7.18-7.14 (m, 1H), 7.11 (dd, J=8.4, 2.1 Hz, 1H),6.87-6.77 (m, 2H), 3.87 (s, 3H), 3.70-3.63 (m, 2H), 3.38 (s, 3H), 2.86(t, =6.4 Hz, 2H), 2.06-1.96 (m, 2H). LCMS M/Z (M+H)₄₂₇.

The following compounds were prepared in a similar fashion to Example21:

Compound Name and Example Structure NMR m/z Example 22

¹H NMR (400 MHz, DMSO-d₆) δ 7.74 (d, J = 0.8 Hz, 1H), 7.64 (d, J = 2.1Hz, 1H), 7.49 (d, J = 0.8 Hz, 1H), 7.37 (d, J = 8.6 Hz, 1H), 7.31 (dd, J= 8.6, 2.2 Hz, 1H), 7.12 (d, J = 1.3 Hz, 1H), 6.88-6.60 (m, 2H), 3.86(s, 3H), 3.62-3.57 (m, 2H), 3.43 (s, 3H), 2.86 (t, J = 6.4 Hz, 2H),2.05- 1.97 (m, 2H). 427 Example 23

¹H NMR (400 MHz, DMSO-d₆) δ 7.94 (d, J = 0.8 Hz, 1H), 7.69 (d, J = 0.8Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.25 (dd, J = 2.1, 1.1 Hz, 1H), 7.17(d, J = 2.1 Hz, 1H), 7.13-7.08 (m, 1H), 7.06 (dd, J = 8.4, 2.2 Hz, 1H),6.68 (d, J = 8.5 Hz, 1H), 3.82 (s, 3H), 3.68-3.61 (m, 2H), 3.37 (s, 3H),2.81 (t, J = 6.6 Hz, 2H), 2.02-1.93 (m, 2H). 377 Example 24

¹H NMR (400 MHz, DMSO-d₆) δ 8.10 (d, J = 0.7 Hz, 1H), 7.83-7.76 (m, 1H),7.53 (d, J = 0.8 Hz, 1H), 7.28 (s, 1H), 7.17 (s, 1H), 7.06 (d, J = 0.7Hz, 1H), 6.81-6.67 (m, 1H), 3.88 (s, 3H), 3.80-3.73 (m, 2H), 3.38-3.34(m, 3H), 3.30-3.28 (m, 3H), 2.83 (t, J = 6.3 Hz, 2H), 2.03- 1.91 (m,2H). 425 Example 25

¹H NMR (400 MHz, DMSO-d₆) δ 7.94 (d, J = 2.1 Hz, 1H), 7.73 (d, J = 0.8Hz, 1H), 7.58 (d, J = 2.1 Hz, 1H), 7.48 (d, J = 0.8 Hz, 1H), 7.11 (s,1H), 6.86-6.59 (m, 1H), 6.53 (s, 1H), 3.86 (s, 3H), 3.64-3.56 (m, 2H),3.37 (s, 3H), 3.34 (s, 3H), 2.93-2.82 (m, 2H), 2.04 (dd, J = 6.5, 4.9Hz, 2H). 425 Example 26

¹H NMR (400 MHz, DMSO-d₆) 7.79 (d, J = 0.8 Hz, 1H), 7.54 (d, J = 0.8 Hz,1H), 7.48 (dd, J = 12.8, 8.1 Hz, 1H), 7.39 (s, 1H), 7.18 (d, J = 1.4 Hz,1H), 6.96-6.69 (m, 2H), 3.88 (s, 3H), 3.81-3.72 (m, 2H), 3.34 (s, 3H),3.28 (s, 3H), 2.83 (t, J = 6.4 Hz, 2H), 1.97 (p, J = 6.3 Hz, 2H). 425

Example 274-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-N-methyl-quinoline-6-carboxamide

Step 1 methyl4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]quinoline-6-carboxylate

To a vial was added7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydroquinoline(Intermediate C, 200 mg, 0.760 mmol), methyl4-bromoquinoline-6-carboxylate (243 mg, 0.912 mmol),dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)(95.2 mg, 0.114 mmol), t-BuONa (146.0 mg, 1.519 mmol) and 1,4-dioxane(1.52 mL). The mixture was sparged with an argon balloon, and thenheated to 120° C. for 16 h under an argon atmosphere. After cooling thereaction to room temperature, DCM (4 mL) was added and the reaction wasfiltered through celite and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (1% TEA in Heptanes to100% EtOAc gradient) to afford the title compound (23.6 g, 7%) as ayellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.92 (d, J=4.9 Hz, 1H), 8.76(dd, J=2.0, 0.6 Hz, 1H), 8.31 (dd, J=8.8, 1.9 Hz, 1H), 8.18 (dd, J=8.8,0.6 Hz, 1H), 7.57 (d, J=0.8 Hz, 1H), 7.45 (d, J=0.7 Hz, 1H), 7.31-7.27(m, 1H), 7.18 (t, J=1.1 Hz, 1H), 6.88 (s, 1H), 6.58-6.30 (m, 1H), 3.96(s, 3H), 3.96 (s, 3H), 3.80 (dd, J=6.7, 4.2 Hz, 2H), 3.03 (t, J=6.6 Hz,2H), 2.18-2.08 (m, 2H).

Step 24-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-N-methyl-quinoline-6-carboxamide

To a solution of methyl4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]quinoline-6-carboxylate(23.4 mg, 0.0522 mmol) in THF (0.5 mL) and water (0.5 mL) was addedlithium hydroxide monohydrate (2.6 mg, 0.063 mmol). The mixture wasstirred at the room temperature for 1 h. After completion of thereaction, the reaction mixture was concentrated under reduced pressure.The resulting residue was dissolved in DMF, and TEA (21.1 mg, 0.209mmol), methylamine hydrochloride (10.6 mg, 0.157 mmol), and TBTU (34.2mg, 0.104 mmol) were added. The mixture was stirred at room temperaturefor 14 h, and then concentrated under reduced pressure. The cruderesidue was purified by reverse phase preparative HPLC (acetonitrile5-50%/0.1% formic acid in water) to give the title compound (13.7 mg,57%, 2 steps) as a yellow solid. H NMR (400 MHz, DMS D) 8.96 (d, J=4.8Hz, 1H), 8.69 (q, J=4.5 Hz, 1H), 8.46 (dd, J=2.0, 0.6 Hz, 1H), 8.19 (dd,J=8.8, 1.9 Hz, 1H), 8.13 (dd, J=8.8, 0.6 Hz, 1H), 7.78 (d, J=0.8 Hz,1H), 7.53 (d, J=0.8 Hz, 1H), 7.45 (d, J=4.8 Hz, 1H), 7.26 (s, 1H),6.87-6.50 (m, 2H), 3.87 (s, 3H), 3.73 (t, J=5.4 Hz, 2H), 3.00 (t, J=6.5Hz, 2H), 2.80 (d, J=4.5 Hz, 3H), 2.19-1.90 (m, 2H). LCMS M/Z (M+H) 448.

The following compounds were prepared in a similar fashion to Example27:

Compound Name and Example Structure NMR m/z Example 28

¹H NMR (400 MHz, CDCl₃) δ 8.85 (d, J = 4.9 Hz, 1H), 8.76 (dd, J = 2.0,0.6 Hz, 1H), 8.27 (dd, J = 8.8, 1.9 Hz, 1H), 8.14 (dd, J = 8.8, 0.6 Hz,1H), 7.69 (d, J = 0.8 Hz, 1H), 7.52 (d, J = 0.8 Hz, 1H), 7.28-7.27 (m,1H), 7.23 (d, J = 4.9 Hz, 1H), 7.03 (dd, J = 8.4, 2.2 Hz, 1H), 6.57 (d,J = 8.4 Hz, 1H), 3.93 (d, J = 3.4 Hz, 6H), 3.83-3.78 (m, 2H), 3.01 (t, J= 6.5 Hz, 2H), 2.13-2.05 (m, 2H). 399 Example 29

¹H NMR (400 MHz, DMSO-d₆) δ 8.86 (d, J = 4.9 Hz, 1H), 8.69-8.61 (m, 1H),8.46 (dd, J = 2.0, 0.6 Hz, 1H), 8.14 (dd, J = 8.8, 1.9 Hz, 1H), 8.08(dd, J = 8.7, 0.6 Hz, 1H), 7.96 (d, J = 0.8 Hz, 1H), 7.71 (d, J = 0.8Hz, 1H), 7.39-7.30 (m, 2H), 7.06 (dd, J = 8.5, 2.2 Hz, 1H), 6.32 (d, J =8.5 Hz, 1H), 3.82 (s, 3H), 3.73 (dd, J = 6.3, 4.7 Hz, 2H), 2.96 (t, J =6.4 Hz, 2H), 2.79 (d, J = 4.5 Hz, 3H), 2.04 (t, J = 5.8 Hz, 2H). 398Example 30

¹H NMR (400 MHz, DMSO-d₆) δ 8.61 (dd, J = 7.6, 0.6 Hz, 1H), 8.39 (s,1H), 8.01 (d, J = 4.7 Hz, 1H), 7.84 (d, J = 0.8 Hz, 1H), 7.77 (dd, J =2.7, 0.7 Hz, 1H), 7.58 (d, J = 0.8 Hz, 1H), 7.28 (d, J = 6.8 Hz, 2H),6.94 (dd, J = 7.6, 2.7 Hz, 2H), 3.89 (s, 3H), 3.71 (t, J = 6.1 Hz, 2H),2.82 (t, J = 6.3 Hz, 2H), 2.75 (d, J = 4.5 Hz, 3H), 2.01 (p, J = 6.3 Hz,2H). 437

Example 315-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-ethyl-3-methyl-benzimidazol-2-one

Step 1 5-bromo-3-methyl-1H-benzimidazol-2-one

To a solution of 2-amino-4-bromobenzenethiol (500 mg, 2.50 mmol) inacetic acid (25 mL) was added triphosgene (490 mg, 1.70 mmol). Themixture was heated at reflux for 18 h. After cooling to roomtemperature, the solution was partially concentrated under reducedpressure, water was added, and the resulting precipitate was removed viafiltration, and washed with aqueous NaOH (1 M). The filtrate wasacidified with aqueous HCl (2 N) to pH 2, and placed in a refrigeratorfor 12 h. The resulting precipitate was filtered, washed with water, anddried under reduced pressure to give the title compound (133 mg, 24%) asa while powder that required no further purification. 1H NMR (400 MHz,DMSO-d₆) δ 10.97 (s, 1H), 7.33 (d, J=1.9 Hz, 1H), 7.13 (dd, J=8.2, 1.9Hz, 1H), 6.91 (d, J=8.2 Hz, 1H), 3.26 (s, 3H).

Step 2 5-bromo-1-ethyl-3-methyl-benzimidazol-2-one

To a solution of 5-bromo-3-methyl-1H-benzimidazol-2-one (30 mg, 0.132mmol) in DMF (1.2 mL) was added NaH (60% in mineral oil, 11.6 mg, 0.291mmol). The resulting mixture was stirred at room temperature for 10 min,and then iodoethane (21.1 μL, 0.26 mmol) was added. The reaction mixturewas stirred for an additional 4 h, and then water (20 mL) was added andthe mixture was extracted with EtOAc (20 mL×3). The combined organiclayers were washed with brine (20 mL), dried over anhydrous Na₂SO₄ andthen concentrated in under reduced pressure. The crude residue waspurified by reverse phase preparative HPLC (acetonitrile 20-60%/0.1%ammonium hydroxide in water) to give the title compound (20.0 mg, 59%).¹H NMR (400 MHz, DMSO-d) S ¹H NMR (400 MHz, DMSO-d₆) δ 7.44-7.39 (m,1H), 7.22 (dd, J=8.3, 1.9 Hz, 1H), 7.16 (dd, J=8.3, 0.4 Hz, 1H), 3.86(q, J=7.2 Hz, 2H), 3.32 (s, 3H), 1.18 (t, J=7.2 Hz, 3H). LCMS M/Z (M+H)255.

Step 25-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-ethyl-3-methyl-benzimidazol-2-one

To a vial was added7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydroquinoline(Intermediate C, 50.0 mg, 0.190 mmol),5-bromo-1-ethyl-3-methyl-benzimidazol-2-one (58.1 mg, 0.228 mmol),dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)(23.8 mg, 0.0285 mmol), t-BuONa (36.5 mg, 0.380 mmol) and 1,4-dioxane(0.4 mL). The mixture was sparged with an argon balloon, and then heatedto 120° C. for 16 h under an argon atmosphere. After cooling thereaction to room temperature, DCM (3 mL) was added and the reaction wasfiltered through celite and concentrated under reduced pressure. Thecrude residue was purified by reverse phase chromatography (acetonitrile20-60%/0.1% ammonium hydroxide in water) to give the title compound(14.1 mg, 32%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆, 22/25 H) δ7.72 (d, J=0.9 Hz, 1H), 7.47 (d, J=0.8 Hz, 1H), 7.25 (d, J=8.3 Hz, 1H),7.14 (d, J=2.0 Hz, 1H), 7.08 (s, 1H), 6.97 (dd, J=8.2, 2.0 Hz, 1H),6.88-6.54 (m, 2H), 3.95-3.79 (m, 5H), 3.65-3.56 (m, 2H), 2.87 (t, J=6.1Hz, 2H), 2.07-1.96 (m, 2H), 1.23 (t, J=7.1 Hz, 3H). LCMS M/Z (M+H) 437.

The following compound was prepared in a similar fashion to Example 31:

Compound Name and Example Structure NMR m/z Example 32

¹H NMR (400 MHz, DMSO-d₆) δ 7.72 (d, J = 0.8 Hz, 1H), 7.47 (d, J = 0.8Hz, 1H), 7.23-7.16 (m, 2H), 7.08 (s, 1H), 6.98 (dd, J = 8.2, 2.0 Hz,1H), 6.64 (s, 2H), 3.86 (d, J = 4.1 Hz, 5H), 3.67-3.56 (m, 2H), 3.37-3.34 (m, 3H), 2.86 (d, J = 6.6 Hz, 2H), 2.08-1.98 (m, 2H), 1.17 (t, J =7.1 Hz, 3H). 438

Example 334-chloro-6-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one

Step 1 6-bromo-4-chloro-1H-benzo[d]imidazol-2(3H)-one

To a solution of 5-bromo-3-chlorobenzene-1,2-diamine (200 mg, 0.90 mmol)in chloroform (3 mL) was added di(1H-imidazol-1-yl)methanone (220 mg,1.35 mmol). The mixture was heated to 60° C. for 12 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the whiteprecipitate was filtered off, washed with chloroform (3 mL×2), and driedin vacuo to give the title compound (170 mg, 76%) as a white solid. ¹HNMR (400 MHz, DMSO-d₆) δ 11.35 (s, 1H), 11.05 (s, 1H), 7.21 (d, J=1.6Hz, 1H), 7.04 (d, J=1.6 Hz, 1H).

Step 2 6-bromo-4-chloro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one

To a stirred solution of 6-bromo-4-chloro-H-benzo[d]imidazol-2(3H)-one(170 mg, 0.69 mmol) in DMF (2 mL) at 0° C. was added NaH (69 mg, 1.72mmol, 60%) and the mixture was stirred for 15 min. Methyliodide (0.13mL, 2.06 mmol) was added dropwise and the mixture stirred at roomtemperature for an additional 12 h. Water (30 mL) was added andextracted with EtOAc (30 mL×3). The combined organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The cruderesidue was purified by silica gel chromatography (petroleumether/EtOAc=5:1) to give the title compound (150 mg, 79%) as a whitesolid. LCMS M/Z (M+H) 275.

Step 34-chloro-6-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one

To a solution of7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline(Intermediate C, 143 mg, 0.54 mmol),6-bromo-4-chloro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one (150 mg,0.54 mmol) and K₃PO₄ (347 mg, 1.63 mmol) in 2-methyl-2-butanol (5 mL)was addedmethanesulfonato(2-dicyclohexylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)(46 mg, 0.054 mmol). The mixture was heated to 95° C. for 12 h under anargon atmosphere. After cooling the reaction to room temperature, themixture was filtered and concentrated in vacuo. The crude residue waspurified by reverse phase chromatography (acetonitrile 35-65%/0.2%formic acid in water) to give the title compound (28 mg, 11%) as ayellow solid. H NMR (400 MHz, CDCl₃) δ 7.55 (s, 1H), 7.42 (s, 1H), 7.07(s, 1H), 6.94 (d, J=1.6 Hz, 1H), 6.88 (s, 1H), 6.80 (d, J=1.6 Hz, 1H),6.49 (t, J=55.6 Hz, 1H), 3.96 (s, 3H), 3.76 (3H), 3.64-3.61 (s, 2H),3.38 (s, 3H), 2.92-2.89 (m, 2H), 2.11-2.09 (m, 2H). LCMS M/Z (M+H)₄₅₈.

The following compound was prepared in a similar fashion to Example 33:

Compound Name and Example Structure NMR m/z Example 34

¹H NMR (400 MHz, CD₃OD) δ 7.73 (s, 1H), 7.48 (s, 1H), 7.02-7.14 (m, 3H),6.72 (t, J = 55.2 Hz, 1H), 6.39 (s, 1H), 3.86 (s, 3H), 3.56-3.41 (m,2H), 3.47 (s, 3H), 3.40 (s, 3H), 2.89- 2.87 (m., 2H), 2.04-2.02 (m, 2H).442 Example 35

¹H NMR (400 MHz, CD₃Cl) δ 7.53 (s, 1H), 7.40 (s, 1H), 7.06 (s, 1H), 6.90(s, 1H), 6.87 (d, J = 11.6 Hz, 1H), 6.58 (s, 1H), 6.47 (t, J = 55.6 Hz,1H), 3.95 (s, 3H), 3.63-3.60 (m, 2H), 3.45 (s, 3H), 3.40 (s, 3H), 2.97-2.92 (m, 2H) 2.17-2.11 (m, 2H). 442

Example 366-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,3,4-trimethyl-1H-benzo[d]imidazol-2(3H)-one

To a solution of4-chloro-6-(7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one(Example 33, 100 mg, 0.22 mmol) in toluene (4 mL) and water (0.4 mL) wasadded potassium methyltrifluoroborate (40 mg, 0.33 mmol),chloro[(di(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II)(15 mg, 0.022 mmol) and Cs₂CO3 (213 mg, 0.66 mmol). The mixture washeated to 100° C. for 16 h under a nitrogen atmosphere. After coolingthe reaction to room temperature, EtOAc (20 mL) was added and washedwith water (20 mL×3) and brine (20 mL). The organic phase was dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude residuewas purified by reverse phase chromatography (acetonitrile 35-65%/0.2%formic acid in water) to give the title compound (7 mg, 7%) as a yellowsolid. ¹H NMR (400 MHz, CDCl₃) δ 7.54 (s, 1H), 7.41 (s, 1H), 7.05 (s,1H), 6.81 (s, 1H), 6.75-6.74 (m, 2H), 6.47 (t, J=55.6 Hz, 1H), 3.95 (s,3H), 3.70 (s, 3H), 3.63 (t, J=5.2 Hz, 2H), 3.37 (s, 3H), 2.91 (t, J=5.2Hz, 2H), 2.61 (s, 3H), 2.14-2.08 (m, 2H). LCMS M/Z (M+H) 438.

The following compound was prepared in a similar fashion to Example 36:

Compound Name and Example Structure NMR m/z Example 37

¹H NMR (400 MHz, CD₃Cl) δ 7.54 (s, 1H), 7.41 (s, 1H), 7.05 (s, 1H), 6.86(s, 1H), 6.81 (s, 1H), 6.75 (s, 1H), 6.47 (t, J = 55.6 Hz, 1H), 3.95 (s,3H), 3.68 (s, 3H), 3.66-3.62 (m, 2H), 3.38 (s, 3H), 2.98-2.88 (m, 4H),2.17-2.07 (m, 2H), 1.30 (t, J = 7.2 Hz, 3H). 452 Example 38

¹H NMR (400 MHz, CD₃Cl) δ 7.54 (s, 1 H), 7.40 (s, 1H), 7.04 (s, 1H),6.81 (s, 1H), 6.74 (s, 1H), 6.74 (s, 1H), 6.47 (t, J = 55.6 Hz, 1H),3.95 (s, 3H), 3.84 (s, 3H), 3.64-3.61 (m, 2H), 3.38 (s, 3H), 2.92-2.90(m, 2H), 2.31-2.25 (m, 1H), 2.13-2.08 (m, 2H), 1.01-0.96 (m, 2H), 0.84-0.80 (m, 2H) 464 Example 39

¹H NMR (400 MHz, DMSO-d₆) δ 7.74 (s, 1 H), 7.49 (s, 1H), 7.09 (s, 1H),7.01 (s, 1H), 7.00 (s, 1H), 6.73 (t, J = 55.6 Hz, 1H), 6.71 (s, 1H),4.14-4.10 (m, 1H), 3.86 (s, 3H), 3.61-3.67 (m, 2H), 3.56 (s, 3H), 3.29(s, 3H), 2.90-2.78 (m, 2H), 2.37-2.26 (m, 2H), 2.21-2.09 (m, 2H),2.07-2.01 (m, 2H), 2.00-1.76 (m, 2H) 478 Example 40

¹H NMR (400 MHz, DMSO-d₆) δ 7.70 (s, 1H), 7.46 (s, 1H), 7.03-7.14 (m,2H), 6.96-6.94 (m, 1H), 6.67 (t, J = 55.2 Hz, 1H), 6.14 (s, 1H), 3.85(s, 3H), 3.61 (s., 3H), 3.45-3.54 (m, 2H), 3.34 (s, 3H), 2.97-2.55 (m,2H), 2.40 (s, 3H), 2.20-1.90 (m, 2H) 438

Example 416-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4-(dimethylamino)-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one

To a solution of4-chloro-6-(7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one(Example 33, 100 mg, 0.22 mmol) in 1,4-dioxane (2 mL) was addeddimethylamine (0.44 mL, 0.87 mmol),dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)(17 mg, 0.022 mmol) and t-BuONa (63 mg, 0.66 mmol). The mixture wasirradiated in a microwave at 120° C. for 0.5 h. DCM (15 mL) was addedand washed with water (15 mL×2), brine (15 mL). The organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude residue was purified by reverse phase chromatography (acetonitrile48-78%/0.05% NH₄OH in water) to give the title compound (17 mg, 16%) asa white solid. H NMR (400 MHz, CDCl₃) δ 7.54 (s, 1H), 7.41 (s, 1H), 7.05(s, 1H), 6.90 (s, 1H), 6.80 (s, 1H), 6.63 (s, 1H), 6.48 (t, J=56.0 Hz,1H), 3.95 (s, 3H), 3.74 (s, 3H), 3.66 (t, J=5.6 Hz, 2H), 3.37 (s, 3H),2.92 (t, J=5.6 Hz, 2H), 2.72 (s, 6H), 2.15-2.09 (m, 2H). LCMS M/Z (M+H)467.

The following compound was prepared in a similar fashion to Example 41:

Compound Name and Example Structure NMR m/z Example 42

¹H NMR (400 MHz, DMSO-d₆) δ 7.72 (s, 1H), 7.47 (s, 1H), 7.06 (s, 1H),6.72 (s, 1H), 6.72 (t, J = 55.2 Hz, 1H), 6.50 (s, 1H), 6.24 (s, 1H),5.40-5.38 (m, 1H), 3.86 (s, 3H), 3.60-3.57 (m, 2H), 3.59 (s, 3H), 3.24(s, 3H), 2.88-2.83 (m, 2H), 2.66 (d, J = 4.8 Hz, 3H), 2.05-1.96 (m, 2H)453 Example 43

¹H NMR (400 MHz, DMSO-d₆) δ 7.73 (s, 1H), 7.48 (s, 1H), 7.08 (s, 1H),6.85 (s, 1H), 6.79 (s, 1H), 6.72 (s, 1H), 6.71 (t, J = 52.0 Hz, 1H),3.86 (s, 3H), 3.62-3.58 (m, 2H), 3.56 (s, 3H), 3.28 (s, 3H), 3.00-2.92(m, 4H), 2.87-2.83 (m, 2H), 2.03- 1.98 (m, 2H), 1.88-1.84 (m, 4H). 493Example 44

¹H NMR (400 MHz, CDCl₃) δ 7.54 (s, 1H), 7.41 (s, 1H), 7.05 (s, 1H), 6.88(s, 1H), 6.79 (s, 1H), 6.62 (s, 1H), 6.48 (t, J = 55.6 Hz, 1H), 3.95 (s,3H), 3.77 (s, 3H), 3.67-3.63 (m, 2H), 3.37 (s, 3H), 2.93-2.90 (m, 2H),2.20-2.16 (m, 2H), 2.15-2.08 (m, 2H), 1.75-1.73 (m, 4H), 1.63- 1.56 (m,4H) 507 Example 45

¹H NMR (400 MHz, CDCl₃) δ 7.54 (s, 1H), 7.41 (s, 1H), 7.06 (s, 1H), 6.89(s, 1H), 6.83 (s, 1H), 6.71 (s, 1H), 6.70 (t, J = 53.2 Hz, 1H), 3.84 (s,3H), 3.77-3.75 (m, 4H), 3.63- 3.58 (m, 2H), 3.61 (s, 3H), 3.27 (s, 3H),2.86-2.84 (m, 6H), 2.01-1.99 (m, 2H). 509

Example 465-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,3,6-trimethyl-1H-benzo[d]imidazol-2(3H)-one

Step 1 4-bromo-5-chlorobenzene-1,2-diamine

To a solution of 4-bromo-5-chloro-2-nitro-aniline (8.0 g, 31.81 mmol) inEtOAc (20 mL) was added tin(II) chloride dihydrate (0.05 mL, 0.65 mmol).The mixture was heated to 80° C. for 3 h under a nitrogen atmosphere.After cooling the reaction to room temperature, EtOAc (50 mL) was addedand washed with sat. aq. NaHCO₃ (20 mL×2) and brine (20 mL). The organicphase was dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The crude residue was purified by silica gel chromatography(petroleum ether/EtOAc=2:1) to give the title compound (5.5 g, 78%) as ayellow solid. H NMR (400 MHz, DMSO-d₆) δ 6.74 (s, 1H), 6.64 (s, 1H),4.89-4.85 (m, 4H).

Step 2 5-bromo-6-chloro-1H-benzo[d]imidazol-2(3H)-one

To a solution of 4-bromo-5-chlorobenzene-1,2-diamine (1.0 g, 4.52 mmol)in THF (10 mL) was added di(1H-imidazol-1-yl)methanone (1.1 g, 6.77mmol). The mixture was heated to 60° C. for 1 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the whiteprecipitate was filtered off, washed with chloroform (3 mL×2), and driedin vacuo to give the title compound (580 mg, 52%) as a white solid whichwas used in the next step directly without further purification.

Step 3 5-bromo-6-chloro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one

To a stirred solution of 5-bromo-6-chloro-1H-benzo[d]imidazol-2(3H)-one(5.5 g, 22.22 mmol) in DMF (100 mL) at 0° C. was added NaH (2.22 g,55.56 mmol, 60%) and the mixture was stirred for 10 min. Methyliodide(9.46 g, 66.67 mmol) was added dropwise and the mixture stirred at roomtemperature for an additional 12 h. Water (100 mL) was added andextracted with EtOAc (100 mL×3). The combined organic layers were washedwith brine (100 mL×3), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (petroleum ether/EtOAc=4:1) to give the title compound(5.3 g, 87%) as yellow oil. ¹H NMR (400 MHz, DMSO-d) 7.59 (s, 1H), 7.49(s, 1H), 3.31 (s, 6H).

Step 45-chloro-6-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one

To a solution of7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline(Intermediate C, 95 mg, 0.36 mmol),5-bromo-6-chloro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one (100 mg,0.36 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (21 mg,0.04 mmol) in toluene (5 mL) was added t-BuONa (104 mg, 1.09 mmol) andtris(dibenzylideneacetone)dipalladium (33 mg, 0.04 mmol). The mixturewas heated to 130° C. for 16 h under an argon atmosphere. After coolingthe reaction to room temperature, DCM (20 mL) was added and washed withwater (10 mL×3). The organic phase was dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The crude residue was purified bysilica gel chromatography (petroleum ether/EtOAc=2:1) to give the titlecompound (100 mg, 60%) as a yellow solid. LCMS M/Z (M+H) 458.

Step 55-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,3,6-trimethyl-1H-benzo[d]imidazol-2(3H)-one

To a solution of5-chloro-6-(7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one(100 mg, 0.22 mmol) in toluene (4 mL) and water (0.4 mL) was addedpotassium methyltrifluoroborate (40 mg, 0.33 mmol),chloro[(di(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II)(15 mg, 0.022 mmol) and Cs₂CO₃ (213 mg, 0.66 mmol). The mixture washeated to 100° C. for 16 h under a nitrogen atmosphere. After coolingthe reaction to room temperature, EtOAc (20 mL) was added and washedwith water (5 mL×3) and brine (5 mL). The organic phase was dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude residuewas purified by reverse phase chromatography (acetonitrile 40-70%/0.05%NH₄OH in water) to give the title compound (7 mg, 7%) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 7.70 (s, 1H), 7.45 (s, 1H), 7.16 (s, 1H),7.08-7.06 (m, 2H), 6.67 (t, J=55.2 Hz, 1H), 6.10 (s, 1H), 3.85 (s, 3H),3.66-3.57 (m, 1H), 3.34 (s, 4H), 3.29 (s, 3H), 2.94-2.81 (m, 2H), 2.14(s, 3H), 2.09-2.01 (m, 2H). LCMS M/Z (M+H) 438.

The following compound was prepared in a similar fashion to Example 46:P_(G)-3_(M)

Compound Name and Example Structure NMR m/z Example 47

¹H NMR (400 MHz, DMSO-d₆) δ 7.52 (s, 1H), 7.38 (s, 1H), 7.04 (s, 1H),6.95 (s, 1H), 6.80 (s, 1H), 6.44 (t, J = 55.6 Hz, 1H), 6.32 (s, 1H),3.94 (s, 3H), 3.65-3.51 (m, 2H), 3.46 (s, 3H), 3.37 (s, 3H), 3.05-2.87(m, 2H), 2.69-2.52 (m, 2H), 2.24- 2.06 (m, 2H), 1.22 (t, J = 7.6 Hz, 3H)452

The following compound was prepared using procedures similar to thosedescriber herein:

Compound Name and Example Structure NMR m/z Example 49

¹H NMR (400 MHz, DMSO-d₆) δ 9.19 (s, 1H), 8.34-8.31 (m, 2H), 8.13 (s,1H), 8.09 (s, 1H), 8.03 (s, 1H), 7.92-7.88 (m, 2H), 7.81-7.79 (m, 1H),7.68 (d, J = 8.0 Hz, 1H), 7.53-7.51 (m, 1H), 7.43 (d, J = 8.0 Hz, 1H),3.92 (s, 3H), 3.91 (s, 3H), 2.76 (d, J = 4.4 Hz, 3H) 396

Example 505-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(21)-yl)-N,1-dimethyl-1H-indole-3-carboxamide

Step 15-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-methyl-1H-indole-3-carboxylicacid

To a solution of methyl 5-bromo-1-methyl-1H-indole-3-carboxylate (200mg, 0.75 mmol) and7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline(Intermediate C, 235 mg, 0.90 mmol) in 1,4-dioxane (5 mL) was addedchloro(2-dicyclohexylphosphino-2′,6′-di-1-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)(54 mg, 0.07 mmol),2-dicyclohexylphosphino-2′,6′-di-1-propoxy-1,1′-biphenyl (33 mg, 0.07mmol) and t-BuONa (215 mg, 2.24 mmol). The mixture was heated to 120° C.for 12 h under a nitrogen atmosphere. After cooling the reaction to roomtemperature, EtOAc (70 mL) was added and washed with water (60 mL×2).The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (DCM/MeOH=10:1) to give the title compound (100 mg, 31%)as colorless oil. LCMS M/Z (M+H) 437.

Step 25-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N,1-dimethyl-1H-indole-3-carboxamide

To a solution of5-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-methyl-1H-indole-3-carboxylicacid (150 mg, 0.34 mmol) and N,N-diisopropylethylamine (0.18 mL, 1.03mmol) in DMF (2 mL) was addedO-(7-azabenzotriazol-1-yl)-N,N,N′,N-tetramethyluroniumhexafluorophosphate (144 mg, 0.38 mmol) and methylamine hydrochloride(28 mg, 0.41 mmol). The reaction was stirred at room temperature for 1h. EtOAc (50 mL) was added and washed with water (50 mL×3) and brine (50mL). The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by reverse phasechromatography (acetonitrile 38-68%/0.2% formic acid in water) to givethe title compound (22 mg, 14%) as a yellow solid. ¹H NMR (400 MHz,CDCl₃) δ 7.84 (s, 1H), 7.66 (s, 1H), 7.54 (s, 1H), 7.44-7.36 (m, 2H),7.22-7.20 (m, 1H), 7.05 (s, 1H), 6.77 (s, 1H), 6.45 (t, J=56.0 Hz, 1H),5.90-5.88 (m, 1H), 3.95 (s, 3H), 3.84 (s, 3H), 3.71 (t, J=5.6 Hz, 2H),3.02 (d, J=4.4 Hz, 3H), 2.93 (t, J=5.6 Hz, 2H), 2.16-2.11 (m, 2H). LCMSM/Z (M+H) 450.

The following compound was prepared in a similar fashion to Example 50:

Compound Name and Example Structure NMR m/z Example 51

¹H NMR (400 MHz, DMSO-d₆) δ 8.10-8.00 (m, 2H), 7.87-7.86 (m, 1H), 7.72(s, 1H), 7.62-7.60 (m, 1H), 7.47 (s, 1H), 7.16-7.04 (m, 2H), 6.68 (t, J= 55.2 Hz, 1H), 6.51 (s, 1H), 4.25 (q, J = 7.2 Hz, 2H), 3.85 (s, 3H),3.60-3.59 (m, 2H), 2.94-2.86 (m, 2H), 2.75 (d, J = 4.4 Hz, 3H),2.06-2.02 (m, 2H), 1.42 (t, J = 7.2 Hz, 3H) 464

Example 525-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1H-indole-3-carboxamide

Step 1 methyl5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carboxylate

To a solution of methyl 5-bromo-1H-indole-3-carboxylate (800 mg, 3.15mmol) in DMF (3 mL) at 0° C. was added NaH (60%, 139 mg, 3.48 mmol) byportionwise. The mixture was stirred at room temperature for 0.5 h.(2-(Chloromethoxy)ethyl)trimethylsilane (0.61 mL, 3.47 mmol) was addeddropwise and the mixture stirred at room temperature for an additional 3h. The mixture was quenched with water (20 mL) and extracted with EtOAc(20 mL×3). The combined organic layers were washed with brine (20 mL),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude residue was purified by silica gel chromatography (petroleumether/EtOAc=10:1) to give the title compound (800 mg, 66%) as acolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 8.33 (s, 1H), 7.87 (s, 1H),7.43-7.38 (m, 2H), 5.48 (s, 2H), 3.94 (s, 3H), 3.47 (t, J=8.0 Hz, 2H),0.89 (t, J=8.0 Hz, 2H), −0.03 (s, 9H).

Step 25-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carboxylicacid

To a solution of methyl5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carboxylate(200 mg, 0.52 mmol) and7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline(Intermediate C, 164 mg, 0.62 mmol) in 1,4-dioxane (4 mL) was addedchloro(2-dicyclohexylphosphino-2′,6′-di-1-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)(39 mg, 0.05 mmol),2-dicyclohexylphosphino-2′,6′-di-1-propoxy-1,1′-biphenyl (23 mg, 0.05mmol) and t-BuONa (150 mg, 1.56 mmol). The mixture was heated to 120° C.for 12 h under a nitrogen atmosphere. After cooling the reaction to roomtemperature, DCM (40 mL) was added and washed with water (30 mL×2). Theorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo. The crude residue was purified by Prep-TLC (DCM/MeOH=10:1) togive the title compound (100 mg, 35%) as a white solid. LCMS M/Z (M+H)553.

Step 35-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-(2H)-yl)-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carboxamide

To a solution of5-(7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carboxylicacid (140 mg, 0.25 mmol) and N,N-diisopropylethylamine (0.13 mL, 0.76mmol) in DMF (3 mL) was added0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (116 mg, 0.31 mmol) and methylamine hydrochloride(21 mg, 0.31 mmol). The reaction was stirred at room temperature for 2h. EtOAc (50 mL) was added and washed with water (50 mL×3) and brine (50mL). The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (135 mg, 94%) as awhite solid that required no further purification. LCMS M/Z (M+H) 566.

Step 45-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1H-indole-3-carboxamide

To a solution of5-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carboxamide(135 mg, 0.24 mmol) in THF (2 mL) was added TBAF (4.0 mL, 4.0 mmol, 1Min THF). The mixture was heated to 50° C. for 40 h under a nitrogenatmosphere. After cooling to room temperature, the mixture was filteredand concentrated in vacuo. EtOAc (40 mL) was added and washed with water(30 mL×2), brine (30 mL). The organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The crude residue waspurified by reverse phase chromatography (acetonitrile 28-58%/0.05%NH₄OH in water) to give the title compound (28 mg, 26%) as a whitesolid. ¹H NMR (400 MHz, DMSO-Q) 611.61 (s, 1H), 8.02 (d, J=1.2 Hz, 1H),8.00 (d, J=2.8 Hz, 1H), 7.87 (d, J=4.4 Hz, 1H), 7.72 (s, 1H), 7.50 (d,J=8.4 Hz, 1H), 7.47 (s, 1H), 7.07 (s, 1H), 7.05-7.03 (m, 1H), 6.68 (t,J=55.2 Hz, 1H), 6.49 (s, 1H), 3.85 (s, 3H), 3.65-3.55 (m, 2H), 2.91-2.86(m, 2H), 2.75 (d, J=4.4 Hz, 3H), 2.11-1.98 (m, 2H). LCMS M/Z (M+H) 436.

The following compound was prepared in a similar fashion to Example 52:

Compound Name and Example Structure NMR m/z Example 53

¹H NMR (400 MHz, DMSO-d₆) δ 11.54 (s, 1H), 7.97 (d, J = 6.4 Hz, 1H),7.96 (d, J = 3.2 Hz, 1H), 7.88 (s, 1H), 7.84 (d, J = 4.8 Hz, 1H), 7.64(s, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.17 (s, 1H), 7.04-7.01 (m, 1H),6.99-6.96 (m, 1H), 6.28 (d, J = 8.4 Hz, 1H), 3.81 (s, 3H), 3.61-3.53 (m,2H), 2.87-2.84 (m, 2H), 2.75 (d, J = 4.4 Hz, 3H), 2.07-1.96 (m, 2H). 386

Example 547-chloro-5-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-(2H)-yl)-N,1-dimethyl-1H-indole-3-carboxamide

Step 1 1-(5-bromo-7-chloro-1H-indol-3-yl)-2,2,2-trichloroethanone

To a solution of 5-bromo-7-chloro-1H-indole (4.0 g, 17.35 mmol) and2,2,2-trichloroacetyl chloride (7.73 mL, 69.42 mmol) in DCM (20 mL) wasadded pyridine (5.59 mL, 69.42 mmol) dropwise. The mixture was heated to48° C. for 12 h under a nitrogen atmosphere. After cooling to roomtemperature, the mixture was poured into ice water (20 mL) and extractedwith DCM (20 mL×3). The combined organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (9 g, crude) as a brown solid that required no furtherpurification. ¹H NMR (400 MHz, DMSO-d₆) δ 13.27 (s, 1H), 8.64-8.47 (m,1H), 8.29 (d, J=2.0 Hz, 1H), 7.68 (s, 1H).

Step 2 methyl 5-bromo-7-chloro-1H-indole-3-carboxylate

To a solution of1-(5-bromo-7-chloro-1H-indol-3-yl)-2,2,2-trichloroethanone (7.0 g, 18.62mmol) in MeOH (20 mL) was added KOH (1.1 g, 0.02 mol) portionwise. Themixture was stirred at room temperature for 12 h under a nitrogenatmosphere. Water (100 mL) was added and the mixture was acidified withHCl (1 N) to pH 6 and then extracted with EtOAc (100 mL×3). The combinedorganic layers were washed with brine (200 mL), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The crude residue waspurified by silica gel chromatography (petroleum ether/EtOAc=1:1) togive the title compound (2.4 g, 44%) as a brown solid. ¹H NMR (400 MHz,CDCl₃) δ 8.92 (s, 1H), 8.24 (s, 1H), 7.96 (s, 1H), 7.42 (s, 1H), 3.94(s, 3H).

Step 3 methyl 5-bromo-7-chloro-1-methyl-1H-indole-3-carboxylate

To a solution of methyl 5-bromo-7-chloro-1H-indole-3-carboxylate (1.2 g,4.16 mmol) in DMF (10 mL) at 0° C. was added NaH (60%, 249 mg, 6.24mmol) by portionwise. The mixture was stirred at room temperature for0.5 h. Iodomethane (0.39 mL, 6.24 mmol) was added dropwise and themixture stirred at room temperature for an additional 2 h. The mixturewas quenched with water (20 mL) and extracted with EtOAc (20 mL×3). Thecombined organic layers were washed with brine (20 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (0.8 g, 63%) as a light yellow solid. H NMR (400 MHz, CDCl₃) δ8.25 (s, 1H), 7.71 (s, 1H), 7.36 (s, 1H), 4.16 (s, 3H), 3.92 (s, 3H).

Step 4 methyl7-chloro-5-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-methyl-1H-indole-3-carboxylate

To a solution of7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline(Intermediate C, 835 mg, 3.17 mmol), methyl5-bromo-7-chloro-1-methyl-1H-indole-3-carboxylate (800 mg, 2.64 mmol)and K₃PO₄ (1.68 g, 7.93 mmol) in 2-methyl-2-butanol (9 mL) was addedmethanesulfonato(2-dicyclohexylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)(223 mg, 0.26 mmol). The mixture was heated to 95° C. for 16 h under anargon atmosphere. After cooling the reaction to room temperature, themixture was filtered and concentrated in vacuo. The crude residue waspurified by silica gel chromatography (petroleum ether/EtOAc=2:1) togive the title compound (250 mg, 19%) as a yellow solid. LCMS M/Z (M+H)485.

Step 57-chloro-5-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-(2H)-yl)-1-methyl-1H-indole-3-carboxylicacid

To a solution of methyl7-chloro-5-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-methyl-1H-indole-3-carboxylate(70 mg, 0.14 mmol) in MeOH (0.05 mL), THF (2 mL) and Water (0.5 mL) wasadded lithium hydroxide monohydrate (61 mg, 1.44 mmol). The mixture washeated to 50° C. for 12 h under a nitrogen atmosphere. After cooling thereaction to room temperature, the mixture was concentrated in vacuo.Water (10 mL) was added and the mixture was acidified with HCl (2 N) topH 4 and then extracted with DCM (20 mL×3). The combined organic layerswere washed with brine (20 mL), dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo to give the title compound (60 mg, 88%) ascolorless oil that required no further purification. LCMS M/Z (M+H) 471.

Step 67-chloro-5-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N,1-dimethyl-1H-indole-3-carboxamide

To a solution of7-chloro-5-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-methyl-1H-indole-3-carboxylicacid (60 mg, 0.13 mmol) and N,N-diisopropylethylamine (0.033 mL, 0.19mmol) in DMF (2 mL) was addedO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (58 mg, 0.15 mmol) and methylamine hydrochloride (13mg, 0.19 mmol). The reaction was stirred at room temperature for 12 h.EtOAc (30 mL) was added and washed with water (30 mL×3) and brine (30mL). The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by reverse phasechromatography (acetonitrile 30-60%/0.05% NH₄OH in water) to give thetitle compound (10 mg, 16%) as a white solid. H NMR (400 MHz, DMSO-d₆) δ8.04 (s, 1H), 7.97-7.96 (m, 2H), 7.74 (s, 1H), 7.49 (s, 1H), 7.15 (s,1H), 7.11 (s, 1H), 6.72 (t, J=55.2 Hz, 1H), 6.56 (s, 1H), 4.13 (s, 3H),3.86 (s, 3H), 3.62-3.58 (m, 2H), 2.89-2.85 (m, 2H), 2.74 (d, J=4.4 Hz,3H), 2.04-2.01 (m, 2H). LCMS M/Z (M+H) 484.

The following compound was prepared in a similar fashion to Example 54:

Compound Name and Example Structure NMR m/z Example 55

¹H NMR (400 MHz, DMSO-d₆) δ 7.90 (s, 1H), 7.67-7.73 (m, 2H), 7.41-7.48(m, 2H), 7.17-7.24 (m, 1H), 7.09 (s, 1H), 6.69 (t, J = 55.2 Hz, 1H),6.32 (s, 1H), 3.85 (s, 3H), 3.60-3.57 (m, 2H), 3.32 (s, 3H), 2.91-2.87(m, 2H), 2.75 (d, J = 4.4 Hz, 3H), 2.03-2.10 (m, 2H) 468 Example 56

¹H NMR (400 MHz, CDCl₃) δ 7.95 (d, J = 7.6 Hz, 1H), 7.60 (s, 1H), 7.53(s, 1H), 7.40 (s, 1H), 7.18 (d, J = 10.4 Hz, 1H), 7.05 (s, 1H), 6.54 (s,1H), 6.45 (t, J = 55.6 Hz, 1H), 5.82- 5.81 (m, 1H), 3.94 (s, 3H), 3.82(s, 3H), 3.69-3.64 (m, 2H), 3.02 (d, J = 4.8 Hz, 3H), 2.97-2.92 (m, 2H),2.19-2.12 (m, 2H). 468 Example 57

¹H NMR (400 MHz, DMSO-d₆) δ 7.95 (s, 1H), 7.89 (s, 1H), 7.83-7.80 (m,1H), 7.69 (s, 1H), 7.49 (s, 1H), 7.45 (s, 1H), 7.06 (s, 1H), 6.64 (t, J= 55.6 Hz, 1 H), 6.05 (s, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.66-3.61 (m,2H), 2.85-2.95 (m, 2H), 2.73 (d, J = 4.4 Hz, 3H), 2.22 (s, 3H),2.04-2.10 (m, 2H) 464 Example 58

¹H NMR (400 MHz, DMSO-d₆) δ 8.30-8.28 (m, 1H), 8.04 (s, 1H), 7.98 (d, J= 8.8 Hz, 1H), 7.84 (s, 1H), 7.59 (s, 1H), 7.56 (s, 1H), 7.26 (s, 1H),7.02 (d, J = 8.8 Hz, 1H), 6.88 (t, J = 55.2 Hz, 1H), 3.92-3.87 (m, 2H),3.89 (s, 3H), 3.85 (s, 3H), 2.85-2.82 (m, 2H), 2.79 (d, J = 4.8 Hz, 3H),2.01-1.98 (m, 2H). 451 Example 59

¹H NMR (400 MHz, DMSO-d₆) δ 8.73 (s, 1H), 8.09 (s, 1H), 7.93-7.92 (m,1H), 7.84 (s, 1H), 7.77 (s, 1H), 7.52 (s, 1H), 7.15 (s, 1H), 7.00 (s,1H), 6.67 (t, J = 55.2 Hz, 1H), 3.93 (s, 3H), 3.87 (s, 3H), 3.75-3.72(m, 2H), 2.87-2.85 (m, 2H), 2.75 (d, J = 4.4 Hz, 3H), 2.06-1.94 (m, 2H).451 Example 60

¹H NMR (400 MHz, DMSO-d₆) δ 8.42-8.41 (m, 1H), 7.95 (s, 1H), 7.83 (s,1H), 7.57 (s, 1H), 7.56 (s, 1H), 7.25 (s, 1H), 6.88 (s, 1H), 6.87 (t, J= 55.2 Hz, 1H), 4.04 (s, 3H), 3.89 (s, 3H), 3.88-3.91 (m, 2H), 2.85-2.81(m, 2H), 2.75 (d, J = 4.8 Hz, 1H), 2.69 (s, 3H), 1.95-2.01 (m, 2H). 465Example 61

¹H NMR (400 MHz, DMSO-d₆) δ 8.92 (s, 1H), 8.19 (s, 1H), 8.10 (s, 1H),7.84-7.92 (m, 2H), 7.62 (s, 1H), 7.29 (s, 1H), 6.96 (t, J = 55.2 Hz,1H), 4.06-4.12 (m, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 2.85-2.82 (m, 2H),2.77 (d, J = 4.8 Hz, 3H) 1.92- 1.99 (m, 2H). 452

Example 625-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-7-isopropyl-N-methyl-1H-indole-3-carboxamide

Step 1 methyl5-bromo-7-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carboxylate

To a solution of methyl 5-bromo-7-chloro-1H-indole-3-carboxylate (300mg, 1.04 mmol) in DMF (3 mL) at 0° C. was added NaH (60%, 54 mg, 1.35mmol) by portionwise. The mixture was stirred at room temperature for0.5 h. (2-(Chloromethoxy)ethyl)trimethylsilane (0.22 mL, 1.25 mmol) wasadded dropwise and the mixture stirred at room temperature for anadditional 2 h. The mixture was quenched with water (20 mL) andextracted with EtOAc (20 mL×3). The combined organic layers were washedwith brine (20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (petroleum ether/EtOAc=3:1) to give the title compound(330 mg, 76%) as a light yellow solid. LCMS M/Z (M+H) 418.

Step 2 methyl7-chloro-5-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carboxylate

To a solution of methyl5-bromo-7-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carboxylate(500 mg, 1.19 mmol) and7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline(Intermediate C, 380 mg, 1.44 mmol) and K₃PO₄ (760 mg, 3.58 mmol) in2-methyl-2-butanol (10 mL) was addedmethanesulfonato(2-dicyclohexylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)(103 mg, 0.12 mmol). The mixture was heated to 95° C. for 16 h under anitrogen atmosphere. After cooling the reaction to room temperature, themixture was filtered and concentrated in vacuo. EtOAc (50 mL) was addedand washed with water (40 mL×2) and brine (30 mL). The organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude residue was purified by silica gel chromatography (petroleumether/EtOAc=4:1) to give the title compound (350 mg, 49%) as a whitesolid. LCMS M/Z (M+H) 601

Step 3 methyl5-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-7-(prop-1-en-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carboxylate

To a solution of methyl7-chloro-5-(7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carboxylate(100 mg, 0.17 mmol) in THF (3 mL) and water (0.6 mL) was addedchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (13 mg, 0.017 mmol), Na₂CO₃ (53 mg, 0.50 mmol) and4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (42 mg, 0.25mmol). The mixture was heated to 90° C. for 3 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the mixturewas filtered and concentrated in vacuo. The crude residue was purifiedby silica gel chromatography (petroleum ether/EtOAc=1:1) to give thetitle compound (65 mg, 64%) as light yellow oil. LCMS M/Z (M+H) 607.

Step 45-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-7-(prop-1-en-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carboxylicacid

To a solution of methyl5-(7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-7-(prop-1-en-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carboxylate(50 mg, 0.08 mmol) in THF (3 mL) and water (0.5 mL) was added lithiumhydroxide monohydrate (35 mg, 0.08 mmol). The mixture was heated to 50°C. for 12 h under a nitrogen atmosphere. After cooling the reaction toroom temperature, the mixture was concentrated in vacuo. Water (10 mL)was added and the mixture was acidified with HCl (2 N) to pH 4 and thenextracted with DCM (20 mL×3). The combined organic layers were washedwith brine (20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (38 mg, 78%) as a whitesolid that required no further purification. LCMS M/Z (M+H) 593.

Step 55-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-(2H)-yl)-N-methyl-7-(prop-1-en-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carboxamide

To a solution of5-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-7-(prop-1-en-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carboxylicacid (250 mg, 0.42 mmol) and N,N-diisopropylethylamine (0.24 mL, 1.35mmol) in DMF (2 mL) was added0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (177 mg, 0.46 mmol) and methylamine hydrochloride(43 mg, 0.63 mmol). The reaction was stirred at room temperature for 12h. EtOAc (20 mL) was added and washed with water (10 mL×2) and brine (5mL). The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (220 mg, 79%) as awhite solid that required no further purification. LCMS M/Z (M+H) 607.

Step 65-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-7-isopropyl-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carboxamide

To a solution of5-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-7-(prop-1-en-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carboxamide(260 mg, 0.43 mmol) in MeOH (10 mL) was added 10% Pd/C (30 mg). Themixture was stirred at room temperature for 12 h under a hydrogenatmosphere (15 Psi). The mixture was filtered and the filtrate wasconcentrated in vacuo. The crude residue was purified by silica gelchromatography (DCM/MeOH=10:1) to give the title compound (240 mg, 92%)as a light yellow solid. LCMS M/Z (M+H) 608.

Step 75-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-7-isopropyl-N-methyl-1H-indole-3-carboxamide

To a solution of5-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-7-isopropyl-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carboxamide(100 mg, 0.16 mmol) in THF (1 mL) was added TBAF (0.82 mL, 0.82 mmol, 1Min THF). The mixture was heated to 50° C. for 12 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the mixturewas concentrated in vacuo. The crude residue was dissolved in DCM (25mL), washed with water (20 mL×2) and brine (20 mL). The organic layerwas dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude residue was purified by reverse phase chromatography (acetonitrile36-66%/0.2% formic acid in water) to give the title compound (32 mg,41%) as alight yellow solid. ¹H NMR (400 MHz, CDCl₃) 11.59 (s, 1H),8.00-7.99 (m, 1H), 7.86-7.85 (s, 2H), 7.72 (s, 1H), 7.47 (s, 1H), 7.06(s, 1H), 6.94 (s, 1H), 6.68 (t, J=55.6 Hz, 1H), 6.58 (s, 1H), 3.85 (s,3H), 3.84-3.79 (m, 1H), 3.64-3.61 (m, 2H), 2.90-2.85 (m, 2H), 2.75 (d,J=4.4 Hz, 3H), 2.06-2.03 (m, 2H), 1.27 (d, J=7.2 Hz, 6H). LCMS M/Z (M+H)478.

The following compound was prepared in a similar fashion to Example 62:

Compound Name and Example Structure NMR m/z Example 63

¹H NMR (400 MHz, CDCl₃) δ 7.84 (s, 1H), 7.65 (s, 1H), 7.58 (s, 1H), 7.47(s, 1H), 7.45 (s, 1H), 7.10 (s, 1H), 6.70 (t, J = 55.6 Hz, 1H) , 5.91-5.90 (m, 1H), 3.97 (s, 3H), 3.96- 3.94 (m, 2H), 3.39-3.36 (m, 1H), 3.01(d, J = 4.8 Hz, 3H), 2.90-2.86 (m, 2H), 2.08-2.05 (m, 2H), 1.41 (d, J =6.4 Hz, 6H). 479

Example 65-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N,7-dimethyl-1H-pyrrolo[2,3-c]pyridine-3-carboxamide

Step 1 5-chloro-7-methyl-1H-pyrrolo[2,3-c]pyridine

To a solution of 6-chloro-2-methyl-3-nitropyridine (14.0 g, 81.13 mmol)in THF (200 mL) at −78° C. was added vinylmagnesium bromide (284 mL,283.94 mmol) dropwise. The mixture was stirred at −20° C. for 2 h undera nitrogen atmosphere. The mixture was poured into ice water (300 mL)and extracted with EtOAc (200 mL×2). The combined organic layers werewashed with brine (400 mL×3), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (petroleum ether/EtOAc=1:1) to give the title compound(6.5 g, 48%) as a yellow oil. LCMS M/Z (M+H) 167.

Step 2 1-(5-bromo-7-chloro-1H-indol-3-yl)-2,2,2-trichloroethanone

To a solution of 5-chloro-7-methyl-1H-pyrrolo[2,3-c]pyridine (4.0 g,24.01 mmol) and AICl₃ (24.0 g, 180 mmol) in DCM (120 mL) was added2,2,2-trichloroacetyl chloride (13.4 mL, 120.04 mmol) dropwise. Themixture was heated to 48° C. for 2 h under a nitrogen atmosphere. Aftercooling to room temperature, the mixture was poured into ice water (200mL) and extracted with DCM (200 mL×3). The combined organic layers werewashed with brine (300 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (petroleum ether/EtOAc=3:1) to give the title compound(5.0 g, 66%) as a brown solid.

Step 3 methyl 5-chloro-7-methyl-1H-pyrrolo[2,3-c]pyridine-3-carboxylate

To a solution of1-(5-bromo-7-chloro-1H-indol-3-yl)-2,2,2-trichloroethanone (5.0 g, 13.3mmol) in MeOH (50 mL) was added KOH (989 mg, 17.63 mmol) portionwise.The mixture was stirred at room temperature for 2 h under a nitrogenatmosphere. Water (50 mL) was added and the mixture was acidified withHCl (1 N) to pH 6 and then extracted with EtOAc (80 mL×2). The combinedorganic layers were washed with brine (150 mL), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The crude residue waspurified by silica gel chromatography (petroleum ether/EtOAc=1:1) togive the title compound (3.0 g, 83%) as a light yellow solid. LCMS M/Z(M+H) 225.

Step 4 methyl5-chloro-7-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-3-carboxylate

To a solution of methyl5-chloro-7-methyl-H-pyrrolo[2,3-c]pyridine-3-carboxylate (2.5 g, 11.13mmol) in DMF (30 mL) at 0° C. was added NaH (60%, 667 mg, 16.69 mmol) byportionwise. The mixture was stirred at room temperature for 0.5 h.(2-(Chloromethoxy)ethyl)trimethylsilane (1.63 mL, 22.26 mmol) was addeddropwise and the mixture stirred at room temperature for an additional 3h. The mixture was quenched with water (100 mL) and extracted with EtOAc(100 mL×3). The combined organic layers were washed with brine (150 mL),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude residue was purified by silica gel chromatography (petroleumether/EtOAc=3:1) to give the title compound (2.5 g, 63%) as a lightyellow solid. LCMS M/Z (M+H) 355.

Step 5 methyl5-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-7-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-3-carboxylate

To a solution of methyl5-chloro-7-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-3-carboxylate(500 mg, 1.41 mmol) and7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline(Intermediate C, 371 mg, 1.41 mmol) and Cs2CO₃ (1.4 g, 4.23 mmol) in1,4-dioxane (10 mL) was addeddichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)(112 mg, 0.14 mmol). The mixture was heated to 110° C. for 16 h under anitrogen atmosphere. After cooling the reaction to room temperature, themixture was filtered and concentrated in vacuo. EtOAc (50 mL) was addedand washed with water (40 mL×2) and brine (30 mL). The organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude residue was purified by silica gel chromatography (petroleumether/EtOAc=1:1) to give the title compound (550 mg, 67%) as yellow oil.LCMS M/Z (M+H) 582.

Step 65-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-7-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-3-carboxylicacid

To a solution of methyl5-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-7-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-3-carboxylate(550 mg, 0.95 mmol) in MeOH (2 mL), THF (5 mL) and water (1 mL) wasadded lithium hydroxide monohydrate (397 mg, 9.45 mmol). The mixture washeated to 50° C. for 12 h under a nitrogen atmosphere. After cooling thereaction to room temperature, the mixture was concentrated in vacuo.Water (10 mL) was added and the mixture was acidified with HCl (2 N) topH 4 and then extracted with DCM (20 mL×3). The combined organic layerswere washed with brine (20 mL), dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo to give the title compound (500 mg, 93%) asyellow oil. LCMS M/Z (M+H) 568.

Step 75-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-(2H)-yl)-N,7-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-3-carboxamide

To a solution of5-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-7-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-3-carboxylicacid (500 mg, 0.88 mmol) and N,N-diisopropylethylamine (0.44 mL, 2.64mmol) in DMF (5 mL) was added0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (402 mg, 1.06 mmol) and methylamine hydrochloride(89 mg, 1.32 mmol). The reaction was stirred at room temperature for 2h. EtOAc (20 mL) was added and washed with water (20 mL×2) and brine (20mL). The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (DCM/MeOH=20:1) to give the title compound (350 mg, 68%)as yellow oil. LCMS M/Z (M+H) 581.

Step 85-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N,7-dimethyl-1H-pyrrolo[2,3-c]pyridine-3-carboxamide

To a solution of5-(7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N,7-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-3-carboxamide(350 mg, 0.60 mmol) in THF (3 mL) was added TBAF (6.03 mL, 6.03 mmol, 1M in THF). The mixture was heated to 50° C. for 48 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the mixturewas concentrated in vacuo. The crude residue was dissolved in EtOAc (20mL), washed with water (20 mL×2) and brine (20 mL). The organic layerwas dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude residue was purified by reverse phase chromatography (acetonitrile18-48%/0.05% NH₄OH in water) to give the title compound (78 mg, 28%) asa white solid. H NMR (400 MHz, CDCl₃) δ 9.90 (s, 1H), 7.79 (s, 1H), 7.56(s, 1H), 7.54 (s, 1H), 7.43 (s, 1H), 7.36 (s, 1H), 7.07 (s, 1H), 6.53(t, J=55.6 Hz, 1H), 5.93-5.86 (m, 1H), 3.96 (s, 3H), 3.88 (t, J=4.8 Hz,2H), 2.99 (d, J=5.2 Hz, 3H), 2.90-2.83 (m, 2H), 2.68 (s, 3H), 2.07-2.04(m, 2H). LCMS M/Z (M+H) 451.

The following compound was prepared in a similar fashion to Example 64:

Compound Name and Example Structure NMR m/z Example 65

¹H NMR (400 MHz, DMSO-d₆) δ 11.80 (s, 1H), 8.37-8.36 (m, 1H), 8.01 (s,1H), 7.86-7.84 (m, 2H), 7.58-7.56 (m, 2H), 7.26 (s, 1H), 7.09 (d, J =8.8 Hz, 1H), 6.87 (t, J = 55.2 Hz, 1H), 3.89 (s, 3H), 3.30- 3.28 (m,2H), 2.83-2.82 (m, 2H), 2.79 (d, J = 4.8 Hz, 3H), 2.01-1.97 (m, 2H). 437Example 66

¹H NMR (400 MHz, CDCl₃) δ 10.34 (s, 1H), 8.84-8.80 (m, 1H), 8.04 (s,1H), 7.70 (s, 1H), 7.60 (s, 1H), 7.48 (s, 1H), 7.16 (s, 1H), 6.94 (s,1H), 6.56 (t, J = 55.2 Hz, 1H), 3.98 (s, 3H), 3.96-3.94 (m, 2H), 3.04(d, J = 4.4 Hz, 3H), 2.89-2.87 (m, 2H), 2.55 (s, 3H), 2.05-2.14 (m, 2H).451 Example 67

¹H NMR (400 MHz, CDCl₃) δ 10.32 (s, 1H), 8.61 (s, 1H), 7.75 (s, 1H),7.69 (s, 1H), 7.56 (s, 1H), 7.44 (s, 1H), 7.32 (s, 1H) , 7.10 (s, 1H),6.51 (t, J = 55.6 Hz, 1H), 5.87-5.86 (m, 1H), 3.96 (s, 3H), 3.88-3.85(m, 2H), 2.99 (d, J = 4.4 Hz, 3H), 2.90- 2.88 (m, 2H), 2.08-2.05 (m,2H). 437 Example 68

¹H NMR (400 MHz, DMSO-d₆) δ 12.20 (s, 1H), 8.33 (s, 1H), 8.21 (s, 1H),8.14 (s, 1H), 8.02-8.01 (m, 1H), 7.74 (s, 1H), 7.49 (s, 1H), 7.12 (s,1H), 6.71 (t, J = 56.0Hz, 1H), 6.43 (s, 1H), 3.85 (s, 3H), 3.42-3.41 (m,2H), 2.95-2.86 (m, 2H), 2.76 (d, J = 4.8 Hz, 3H), 2.01-1.99 (m, 2H). 437Example 69

¹H NMR (400 MHz, CDCl₃) δ 8.97 (s, 1H), 8.33 (s, 1H), 8.18 (s, 1H),7.99-7.98 (m, 1H), 7.73 (s, 1H), 7.60 (s, 1H), 7.50 (s, 1H), 7.21 (s,1H), 6.58 (t, J = 55.6 Hz, 1H), 4.01- 3.96 (m, 2H), 4.00 (s, 3H), 3.04(d, J = 4.8 Hz, 3H), 2.92-2.87 (m, 2H), 2.17-2.10 (m, 2H) 438 Example 70

¹H NMR (400 MHz, DMSO-d₆) δ 8.79 (s, 1H), 8.18 (s, 1 H), 8.12 (s, 1H),7.95-7.94 (m, 1H), 7.88 (s, 1H), 7.62 (s, 1H), 7.29 (s, 1H), 6.97 (t, J= 55.2 Hz, 1H), 4.06-4.12 (m, 2H), 3.90 (s, 3H), 2.85-2.82 (m, 2H), 2.77(d, J = 4.4 Hz, 3H), 1.99- 1.95 (m, 2H). 438 Example 71

¹H NMR (400 MHz, DMSO-d₆) δ 8.39 (s, 1H), 8.05-8.03 (m, 1H), 7.87 (s,1H), 7.63-7.59 (m, 2H), 7.35-7.30 (m, 2H), 6.92 (t, J = 55.2 Hz, 1H),3.97-3.94 (m, 2H), 3.90 (s, 3H), 2.87 (d, J = 4.8 Hz, 3H), 2.84- 2.81(m, 2H), 2.03-1.96 (m, 2H) 438

Example 726-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methylimidazo[1,2-b]pyridazine-3-carboxamide

Step 1 ethyl6-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-(2H)-yl)imidazo[1,2-b]pyridazine-3-carboxylate

To a solution of7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline(Intermediate C, 700 mg, 2.67 mmol), ethyl6-chloroimidazo[1,2-b]pyridazine-3-carboxylate (600 mg, 2.67 mmol) andK₃PO₄ (1.69 g, 7.98 mmol) in 2-methyl-2-butanol (10 mL) was addedmethanesulfonato(2-dicyclohexylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)(225 mg, 0.27 mmol). The mixture was heated to 95° C. for 12 h under anargon atmosphere. After cooling the reaction to room temperature, themixture was filtered and concentrated in vacuo. The crude residue waspurified by Prep-TLC (petroleum ether/EtOAc=1:1) to give the titlecompound (110 mg, 9%) as yellow oil. LCMS M/Z (M+H) 453.

Step 26-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)imidazo[1,2-b]pyridazine-3-carboxylicacid

To a solution of ethyl6-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)imidazo[1,2-b]pyridazine-3-carboxylate(110 mg, 0.28 mmol) in MeOH (1 mL), THF (3 mL) and water (0.5 mL) wasadded lithium hydroxide monohydrate (116 mg, 2.76 mmol). The mixture washeated to 50° C. for 12 h under a nitrogen atmosphere. After cooling thereaction to room temperature, the mixture was concentrated in vacuo.Water (10 mL) was added and the mixture was acidified with HCl (2 N) topH 4 and then extracted with DCM (20 mL×3). The combined organic layerswere washed with brine (20 mL), dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo to give the title compound (80 mg, 78%) asyellow oil that required no further purification. LCMS M/Z (M+H) 425.

Step 36-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methylimidazo[1,2-b]pyridazine-3-carboxamide

To a solution of6-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)imidazo[1,2-b]pyridazine-3-carboxylicacid (80 mg, 0.19 mmol) and N,N-diisopropylethylamine (0.09 mL, 0.57mmol) in DMF (2 mL) was added0-(7-azabenzotriazol-1-yl)-N,N,N′,N-tetramethyluroniumhexafluorophosphate (86 mg, 0.23 mmol) and methylamine hydrochloride (19mg, 0.28 mmol). The reaction was stirred at room temperature for 2 h.EtOAc (20 mL) was added and washed with water (20 mL×2) and brine (20mL). The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by reverse phasechromatography (acetonitrile 37-67%/0.05% NH₄OH in water) to give thetitle compound (19 mg, 22%) as a yellow solid. H NMR (400 MHz, CDCl₃) δ8.46-8.40 (m, 1H), 8.33 (s, 1H), 7.89 (s, 1H), 7.86 (s, 1H), 7.61 (d,J=12 Hz, 1H), 7.52 (s, 1H), 7.24 (s, 1H), 6.60 (t, J=55.6 Hz, 1H), 4.00(s, 3H), 3.95 (t, J=6.4 Hz, 2H), 3.03 (d, J=4.8 Hz, 3H), 2.86 (t, J=6.4Hz, 2H), 2.19-2.12 (m, 2H). LCMS M/Z (M+H) 438.

The following compound was prepared in a similar fashion to Example 72:

Compound Name and Example Structure NMR m/z Example 73

¹H NMR (400 MHz, DMSO-d₆) δ 8.52 (s, 1H), 8.32-8.31 (m, 1H), 7.92 (s,1H), 7.73-7.71 (m, 2H), 7.48 (s, 1H), 7.27 (d, J = 7.6 Hz, 1H), 7.11 (s,1H), 6.70 (t, J = 55.2 Hz, 1H), 6.57 (s, 1H), 3.85 (s, 3H), 3.63-3.60(m, 2H), 2.91-2.85 (m, 2H), 2.78 (d, J = 4.0 Hz, 3H), 2.07-2.00 (m, 2H).437

Example 747-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1-(7-(1-methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroquinoline

Step 1 2-bromo-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine

To a stirred solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (1.0 g, 5.05mmol) in THF (10 mL) at 0° C. was added NaH (225 mg, 5.63 mmol, 60%) andthe mixture was stirred for 30 min. Benzenesulfonyl chloride (0.72 mL,5.66 mmol) was added dropwise and the mixture stirred at roomtemperature for an additional 2 h. The mixture was quenched with sat.aq. NH₄C (30 mL) and extracted with EtOAc (30 mL×2). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (1.4 g, 82%) as ayellow solid that required no further purification. ¹H NMR (400 MHz,CD₃OD) δ 8.45 (s, 1H), 8.24 (d, J=4.0 Hz, 1H), 8.20-8.15 (m, 2H),7.74-7.67 (m, 1H), 7.64-7.59 (m, 2H), 6.85 (d, J=4.0 Hz, 1H).

Step 27-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-1-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroquinoline

To a solution of 2-bromo-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine(500 mg, 1.48 mmol) and7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline(Intermediate C, 468 mg, 1.78 mmol) in 1,4-dioxane (10 mL) was addedchloro(2-dicyclohexylphosphino-2′,6′-di-1-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)(116 mg, 0.15 mmol),2-dicyclohexylphosphino-2′,6′-di-1-propoxy-1,1′-biphenyl (70 mg, 0.15mmol) and t-BuONa (710 mg, 7.39 mmol). The mixture was heated to 120° C.for 12 h under a nitrogen atmosphere. After cooling the reaction to roomtemperature, DCM (60 mL) was added and washed with water (40 mL×2). Theorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo. The crude residue was purified by silica gel chromatography(DCM/MeOH=99:1) to give the title compound (292 mg, 52%) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.22 (s, 1H), 7.72 (d, J=3.6 Hz, 1H),7.70 (s, 1H), 7.57 (s, 1H), 7.22 (s, 1H), 7.17 (s, 1H), 6.60 (t, J=56.0Hz, 1H), 6.56 (d, J=4.4 Hz, 1H), 3.96 (s, 3H), 3.90 (t, J=6.0 Hz, 2H),2.95 (t, J=6.0 Hz, 2H), 2.15-2.09 (m, 2H).

Step 31-(7-bromo-5H-pyrrolo[2,3-b]pyrazin-2-yl)-7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline

To a solution of7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-1-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroquinoline(200 mg, 0.53 mmol) in DMF (2 mL) at 0° C. was added N-bromosuccinimide(89 mg, 0.47 mmol) portionwise. The mixture was stirred at roomtemperature for 1 h. The mixture was poured into water (50 mL) andextracted with DCM (50 mL×2). The combined organic layers were driedover Na₂SO₄, filtered and concentrated in vacuo. The crude residue waspurified by silica gel chromatography (DCM/MeOH=49:1) to give the titlecompound (132 mg, 55%) as a yellow solid. H NMR (400 MHz, DMSO-d) S12.36 (s, 1H), 8.27 (s, 1H), 7.99 (d, J=2.4 Hz, 1H), 7.83 (s, 1H), 7.57(s, 1H), 7.39 (s, 1H), 7.25 (s, 1H), 6.84 (t, J=54.8 Hz, 1H), 3.92-3.81(m, 2H), 3.89 (s, 3H), 2.86 (t, J=6.0 Hz, 2H), 2.07-1.93 (m, 2H).

Step 47-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1-(7-(1-methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,2,3,4-tetrahydroquinoline

To a solution of1-(7-bromo-5H-pyrrolo[2,3-b]pyrazin-2-yl)-7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline(150 mg, 0.33 mmol) in THF (5 mL) and water (1 mL) was added1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (82mg, 0.39 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl(14 mg, 0.03 mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (24 mg, 0.03 mmol) and Na₂CO₃ (105 mg, 0.99 mmol). Thereaction mixture was heated to 60° C. for 12 h under a nitrogenatmosphere. After cooling to room temperature, the mixture was filteredand concentrated in vacuo. DCM (30 mL) was added and washed with water(30 mL×2). The organic layer was dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo. The crude residue was purified by reversephase chromatography (acetonitrile 42-52%/0.05% NH₄OH in water) to givethe title compound (20 mg, 13%) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.90 (d, J=2.4 Hz, 1H), 8.23 (s, 1H), 8.10 (s, 1H), 8.02 (d,J=3.2 Hz, 1H), 7.92 (s, 1H), 7.83 (s, 1H), 7.58 (s, 1H), 7.55 (s, 1H),7.25 (s, 1H), 6.87 (t, J=52.0, 1H), 3.93 (t, J=6.0 Hz, 2H), 3.89 (s,3H), 3.85 (s, 3H), 2.87 (t, J=6.0 Hz, 2H), 2.08-1.98 (m, 2H). LCMS M/Z(M+Na) 483.

The following compound was prepared in a similar fashion to Example 74:

Compound Name and Example Structure NMR m/z Example 75

¹H NMR (400 MHz, DMSO-d₆) δ 11.79 (s, 1H), 8.18 (s, 1H), 8.15 (s, 1H),8.01 (s, 1H), 7.97-7.92 (m, 2H), 7.76 (s, 1H), 7.34 (s, 1H), 7.26-7.20(m, 1H), 7.18-7.13 (m, 1H), 3.94-3.91 (m, 2H), 3.87 (s, 3H), 3.84 (s,3H), 2.84-2.80 (m, 2H), 2.03-1.97 (m, 2H). 411

Example 767-(2-(difluoromethyl)-6-methyl-3-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxamide

Step 1 tert-butyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate

To a solution of tert-butyl7-bromo-2,3-dihydrobenzo[/][1,4]oxazepine-4(5H)-carboxylate (800 mg,2.44 mmol) in 1,4-dioxane (5 mL) was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.24 g,4.88 mmol), KOAc (718 mg, 7.31 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(I) (178 mg, 0.24mmol). The mixture was heated to 90° C. for 3 h under a nitrogenatmosphere. After cooling to room temperature, EtOAc (60 mL) was addedand washed with water (50 mL×2). The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude residuewas purified by silica gel column chromatography (petroleumether/EtOAc=3:1) to give the title compound (710 mg, 78%) as a whitesolid. LCMS M/Z (M+Na) 398.

Step 2 2-bromo-4-chloro-3-(difluoromethyl)-1-methylbenzene

To a solution of 2-bromo-6-chloro-3-methylbenzaldehyde (300 mg, 1.28mmol) in DCM (10 mL) at 0° C. was added diethylaminosulfur trifluoride(0.34 mL, 2.57 mmol) dropwise. The mixture was stirred at roomtemperature for 1 h under a nitrogen atmosphere. The reaction wasquenched with water (5 mL) and extracted with DCM (10 mL×3). Thecombined orgnic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by silica gelcolumn chromatography (petroleum ether/EtOAc=100:1) to give the titlecompound (210 mg, 64%) as colorless oil. ¹H NMR (400 MHz, CD₃OD) δ7.39-7.38 (m, 2H), 7.35 (t, J=52.0 Hz, 1H), 2.42 (s, 3H).

Step 3 tert-butyl7-(3-chloro-2-(difluoromethyl)-6-methylphenyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate

To a solution of tert-butyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzo[/][1,4]oxazepine-4(5H)-carboxylate(709 mg, 1.89 mmol) and2-bromo-4-chloro-3-(difluoromethyl)-1-methylbenzene (460 mg, 1.8 mmol)in 1,4-dioxane (5 mL) and water (1 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (131 mg,0.18 mmol) and Na₂CO₃ (572 mg, 5.4 mmol). The mixture was irradiated ina microwave at 90° C. for 0.5 h. EtOAc (70 mL) was added and washed withwater (60 mL×2), brine (60 mL). The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude residuewas purified by silica gel column chromatography (petroleumether/EtOAc=3:1) to give the title compound (400 mg, 52%) as a whitesolid. ¹H NMR (400 MHz, CD₃OD) δ 7.44-7.38 (m, 2H), 7.16-7.06 (m, 1H),7.05-6.94 (m, 2H), 6.54 (t, J=54.0 Hz, 1H), 4.58-4.41 (m, 2H), 4.22-4.00(m, 2H), 3.93-3.71 (m, 2H), 2.03-1.97 (m, 3H), 1.39-1.35 (m, 9H).

Step 4 tert-butyl7-(2-(difluoromethyl)-6-methyl-3-(1-methyl-1H-pyrazol-4-yl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate

To a solution of tert-butyl7-(3-chloro-2-(difluoromethyl)-6-methylphenyl)-2,3-dihydrobenzo[][1,4]oxazepine-4(5H)-carboxylate (200 mg, 0.47 mmol) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(196 mg, 0.94 mmol) in THF (5 mL) and water (1 mL) was added2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (22 mg, 0.05mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (37 mg, 0.04 mmol) and Na₂CO₃ (150 mg, 1.42 mmol). Themixture was irradiated in a microwave at 60° C. for 0.5 h. EtOAc (70 mL)was added and washed with water (60 mL×2), brine (60 mL). The organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The crude residue was purified by silica gel columnchromatography (petroleum ether/EtOAc=3:1) to give the title compound(210 mg, 95%) as colourless oil. LCMS M/Z (M+H) 470.

Step 57-(2-(difluoromethyl)-6-methyl-3-(1-methyl-1H-pyrazol-4-yl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine

To a solution of tert-butyl7-(2-(difluoromethyl)-6-methyl-3-(1-methyl-H-pyrazol-4-yl)phenyl)-2,3-dihydrobenzo[/][1,4]oxazepine-4(5H)-carboxylate(210 mg, 0.45 mmol) in DCM (2 mL) was added trifluoroacetic acid (0.33mL, 4.47 mmol). The reaction mixture was stirred at room temperature for12 h and concentrated in vacuo. DCM (50 mL) was added, washed with sat.aq. NaHCO₃ (30 mL×2) and water (30 mL). The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (140 mg, 85%) as brown oil that required no furtherpurification. LCMS M/Z (M+H) 370.

Step 67-(2-(difluoromethyl)-6-methyl-3-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxamide

To a solution of7-(2-(difluoromethyl)-6-methyl-3-(1-methyl-H-pyrazol-4-yl)phenyl)-2,3,4,5-tetrahydrobenzo[][1,4]oxazepine (140 mg, 0.38 mmol) andN-methyl-H-imidazole-1-carboxamide (71 mg, 0.57 mmol) in DCM (3 mL) wasadded triethylamine (0.16 mL, 1.14 mmol). The reaction mixture wasstirred at room temperature for 12 h and concentrated in vacuo. DCM (50mL) was added and washed with water (40 mL×2). The organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude residue was purified by Prep-TLC (DCM/MeOH=10:1) to give the titlecompound (35 mg, 21%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.62(s, 1H), 7.52 (s, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H),7.12-7.06 (m, 3H), 6.48 (t, J=54.0 Hz, 1H), 4.54-4.32 (m, 3H), 4.27-4.18(m, 1H), 4.16-4.06 (m, 2H), 3.98 (s, 3H), 3.78-3.72 (m, 1H), 2.75 (d,J=4.0 Hz, 3H), 2.07 (s, 3H). LCMS M/Z (M+Na) 449.

The following compound was prepared in a similar fashion to Example 76:

Compound Name and Example Structure NMR m/z Example 77

¹H NMR (400 MHz, DMSO-d₆) δ 7.89 (s, 1H), 7.60 (s, 1H), 7.59- 7.53 (m,1H), 7.46-7.44 (m, 1H), 7.37 (s, 1H), 7.26 (d, J = 7.6 Hz, 1H),7.16-7.15 (m, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.66 (t, J = 54.4 Hz, 1H),6.53-6.50 (m, 1H), 4.50 (s, 2H), 4.08-4.02 (m, 2H), 3.90 (s, 3H),3.75-3.70 (m, 2H), 2.50 (s, 3H). 413

Example 781-(7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl-3,4-dihydroquinolin-1(2H)-yl)-2,3-dihydrobenzo[f]I[1,4]oxazepin-4(5H)-yl)propan-1-on

Step 1 7-bromo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine

To a solution of tert-butyl7-bromo-2,3-dihydrobenzo[/][1,4]oxazepine-4(5H)-carboxylate (2.0 g, 6.09mmol) in DCM (20 mL) was added trifluoroacetic acid (4.51 mL, 60.94mmol) dropwised. The reaction mixture was stirred at room temperaturefor 1 h and concentrated in vacuo. The residue was diluted with DCM (30mL), washed with sat. aq. NaHCO₃ (30 mL×2) and water (30 mL). Theorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo to give the title compound (1.4 g, crude) as yellow oil thatrequired no further purification. LCMS M/Z (M+Na) 228.

Step 2 1-(7-bromo-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)propan-1-one

To a solution of 7-bromo-2,3,4,5-tetrahydrobenzo[/][1,4]oxazepine (1.4g, 6.14 mmol) and triethylamine (2.52 mL, 18.41 mmol) in DCM (30 mL) at0° C. was added a solution of propionyl chloride (0.8 mL, 9.21 mmol) inDCM (2 mL) dropwise. The reaction mixture was stirred at 20° C. for 10min and concentrated in vacuo. The crude residue was purified by silicagel column chromatography (eluent from petroleum ether/EtOAc=100:1 to1:1) to give the title compound (1.15 g, 66%) as yellow oil. LCMS M/Z(M+H) 285.

Step 31-(7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)propan-1-one

To a solution of1-(7-bromo-2,3-dihydrobenzo[/][1,4]oxazepin-4(5H)-yl)propan-1-one (300mg, 1.06 mmol),7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydroquinoline(Intermediate C, 278 mg, 1.06 mmol) and t-BuONa (254 mg, 2.64 mmol) in1,4-dioxane (6 mL) was addeddichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)(84 mg, 0.11 mmol). The reaction mixture was heated to 120° C. for 16 hunder a nitrogen atmosphere. After cooling to room temperature, themixture was filtered and concentrated in vacuo. The crude residue waspurified by reverse phase chromatography (acetonitrile 44-74%/0.2%formic acid in water) to give the title compound (67 mg, 14%) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.75 (s, 1H), 7.49 (s, 1H), 7.34-6.98(m, 4H), 6.90-6.58 (m, 2H), 4.60-4.55 (m, 2H), 4.20-4.00 (m, 2H),3.88-3.78 (m, 5H), 3.63-3.51 (m, 2H), 2.86-2.82 (m, 2H), 2.39-2.22 (m,2H), 2.00-1.96 (m, 2H), 0.97-0.91 (m, 3H). LCMS M/Z (M+Na) 489.

The following compound was prepared in a similar fashion to Example 78:

Compound Name and Example Structure NMR m/z Example 79

¹H NMR (400 MHz, DMSO-d₆) δ 7.91 (s, 1H), 7.67 (d, J = 2.2 Hz, 1H),7.28-6.91 (m, 5H), 6.54-6.43 (m, 1H), 4.60-4.48 (m, 2H), 4.17- 3.96 (m,2H), 3.86-3.78 (m, 2H), 3.82 (s, 3H), 3.53-3.51 (m, 2H), 2.79 (t, J =6.4 Hz, 2H), 2.39-2.31 (m, 2H), 2.05-1.85 (m, 2H), 0.94 (t, J = 7.6 Hz,3H). 417

Example 80(S)-5-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-3-methyl-3,4-dihydroquinoxalin-2(1H)-one

Step 17-(difluoromethyl)-1-(2-fluoro-3-nitrophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline

To a solution of 1-bromo-2-fluoro-3-nitrobenzene (100 mg, 0.45 mmol) and7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline(Intermediate C, 92 mg, 0.35 mmol) in 1,4-dioxane (2 mL) was addedCs₂CO₃ (228 mg, 0.70 mmol) and palladium(II) acetate (8 mg, 0.04 mmol).The mixture was irradiated in a microwave at 140° C. for 1 h. Themixture was filtered and concentrated in vacuo. The crude residue waspurified by Prep-TLC (petroleum ether/EtOAc=1:1) to give the titlecompound (40 mg, 22%) as red oil. LCMS M/Z (M+H) 403.

Step 2(S)-2-((2-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-(2H)-yl)-6-nitrophenyl)amino)propanoicacid

To a solution of7-(difluoromethyl)-1-(2-fluoro-3-nitrophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline(40 mg, 0.10 mmol) in DMF (3 mL) was added (S)-2-aminopropanoic acid (13mg, 0.15 mmol) and Cs₂CO₃ (65 mg, 0.20 mmol). The reaction mixture washeated to 100° C. for 4 h. After cooling to room temperature, EtOAc (30mL) was added and washed water (20 mL×3). The combined aqueous layerswere acidified with HCl (2 N) to pH 4 and then extracted with EtOAc (40mL×3). The combined organic layers were washed with brine (30 mL×3),dried over anhydrous Na₂SO₄ and concentrated in vacuo to give the titlecompound (24 mg, 51%) as a brown solid that required no furtherpurification. LCMS M/Z (M+H) 472.

Step 3(S)-5-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-3-methyl-3,4-dihydroquinoxalin-2(1H)-one

To a solutionof(S)-2-((2-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-nitrophenyl)amino)propanoicacid (40 mg, 0.08 mmol) in AcOH (2 mL) was added Fe powder (24 mg, 0.42mmol). The reaction mixture was heated to 100° C. for 12 h under anitrogen atmosphere. After cooling to room temperature, the mixture wasfiltered and concentrated in vacuo. The crude residue was purified byreverse phase chromatography (acetonitrile 36-56%/0.2% fomic acid inwater) to give the title compound (2 mg, 5%) as a yellow solid. ¹H NMR(400 MHz, DMSO-d₆) δ 10.37 (s, 1H), 7.71 (s, 1H), 7.46 (s, 1H),7.14-7.03 (m, 1H), 6.87-6.55 (m, 4H), 6.34-6.25 (m, 1H), 5.43-5.40 (m,1H), 4.01-3.72 (m, 1H), 3.86 (s, 3H), 2.89-2.85 (m, 2H), 2.27-1.91 (m,4H), 1.30-1.06 (m, 3H). LCMS M/Z (M+H) 424.

The following compound was prepared in a similar fashion to Example 80:

Compound Name and Example Structure NMR m/z Example 81

¹H NMR (400 MHz, DMSO-d₆) δ 10.36 (s, 1H), 7.73 (s, 1H), 7.48 (s, 1H),7.22-7.02 (m, 1H), 6.89-6.51 (m, 4H), 6.45-6.24 (m, 1H), 5.41 (d, J =12.8 Hz, 1H), 3.91-3.66 (m, 1H), 3.86 (s, 3H), 3.50-3.36 (m, 2H),2.89-2.85 (m, 2H), 2.33-1.94 (m, 2H), 1.28-1.07 (m, 3H). 424 Example 82

¹H NMR (400 MHz, CD₃OD) δ 7.90(s, 1H), 7.65 (s, 1H), 7.47 (s, 1H), 7.17(s, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.88-6.85 (m, 1H), 6.82-6.77 (m, 1H),6.66 (d, J = 7.6 Hz, 1H), 6.25 (s, 1H), 4.27 (s, 1H), 4.05-3.95 (m, 1H),3.91 (s, 3H), 3.45-3.42 (m, 2H), 2.97-2.92 (m, 2H), 2.15-2.11 (m, 2H),1.41-1.39 (m, 3H). 374

Example 833-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-carboxamide

Step 1 methyl3-bromo-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-carboxylate

To a solution of methyl 3-bromo-1H-indazole-5-carboxylate (2.0 g, 7.8mmol) and Cs₂CO₃ (5.1 g, 15.7 mmol) in DMF (10 mL) was addedtetrahydro-2H-pyran-4-yl methanesulfonate (2.1 g, 11.7 mmol). Thereaction was heated to 80° C. for 12 h. After cooling to roomtemperature, the reaction was concentrated in vacuo. EtOAc (80 mL) wasadded and washed with water (100 mL×3), brine (100 mL). The organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The crude residue was purified by silica gel chromatography(petroleum ether/EtOAc=10:1) to give the title compound (400 mg, 15%) asa yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.39 (s, 1H), 8.12-8.09 (m,1H), 7.47 (d, J=8.8 Hz, 1H), 4.67-4.59 (m, 1H), 4.20-4.16 (m, 2H), 3.97(s, 3H), 3.67-3.55 (m, 2H), 2.47-2.36 (m, 2H), 2.00-1.96 (m, 2H).

Step 23-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-carboxylicacid

To a solution of methyl3-bromo-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-carboxylate (500 mg,1.47 mmol),7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline(Intermediate C, 388 mg, 1.47 mmol) in 1,4-dioxane (10 mL) was addedchloro(2-dicyclohexylphosphino-2′,6′-di-1-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)(115 mg, 0.15 mmol),2-dicyclohexylphosphino-2′,6′-di-1-propoxy-1,1′-biphenyl (69 mg, 0.15mmol) and t-BuONa (425 mg, 4.4 mmol). The reaction mixture was heated to120° C. for 16 h under a nitrogen atmosphere. After cooling to roomtemperature, the reaction was concentrated in vacuo. EtOAc (30 mL) wasadded and washed with water (10 mL×3), brine (10 mL). The organic layerwas dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude residue was purified by Prep-TLC (DCM/MeOH=20:1) to give the titlecompound (320 mg, 43%) as a yellow solid. LCMS M/Z (M+H) 508.

Step 33-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-carboxamide

To a solution of3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-carboxylicacid (300 mg, 0.59 mmol) in DCM (5 mL) was addedN,N-diisopropylethylamine (0.314 mL, 1.77 mmol), HATU (337 mg, 0.89mmol) and methanamine (1.2 mL, 1.2 mmol, 1 M in THF). The reaction wasstirred at room temperature for 2 h and concentrated in vacuo. EtOAc (30mL) was added and washed with water (10 mL×3), brine (10 mL). Theorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo. The crude residue was purified by reverse phase chromatography(acetonitrile 30-60%/0.05% NH₄OH in water) to give the title compound(11 mg, 55%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.45-8.42 (m,1H), 8.07 (s, 1H), 7.93-7.88 (m, 1H), 7.86-7.80 (m, 1H), 7.77 (s, 1H),7.52 (s, 1H), 7.19 (s, 1H), 6.94 (s, 1H), 6.74 (t, J=56 Hz, 1H),4.96-4.90 (m, 1H), 4.02-3.99 (m, 2H), 3.90-3.81 (m, 2H), 3.87 (s, 3H),3.59-3.54 (m, 2H), 2.96-2.92 (m, 2H), 2.76 (d, J=4.4 Hz, 3H), 2.16-2.03(m, 4H), 1.93-1.90 (m, 2H). LCMS M/Z (M+H) 521.

The following compound was prepared in a similar fashion to Example 83:

Compound Name and Example Structure NMR m/z Example 84

¹H NMR (400 MHz, DMSO-d₆) δ 8.42-8.41 (m, 1H), 7.98 (s, 1H), 7.94 (s,1H), 7.90-7.85 (m, 1H), 7.81-7.77 (m, 1H), 7.70 (s, 1H), 7.28 (s, 1H),7.08 (d, J = 8.4 Hz, 1H), 6.53 (d, J = 8.4 Hz, 1H), 4.92- 4.86 (m, 1H),4.02-4.00 (m, 2H), 3.86-3.75 (m, 2H), 3.82 (s, 3H), 3.59-3.53 (m, 2H),2.93-2.86 (m, 2H), 2.74 (d, J = 4.4 Hz, 3H), 2.20- 2.00 (m, 4H),1.92-1.90 (m, 2H). 471

Example 85

N,1-dimethyl-7-(o-tolyl)-3,5-dihydro-2H-1,4-benzodiazepine-4-carboxamide

To a solution of7-bromo-N-methyl-1,2,3,5-tetrahydro-1,4-benzodiazepine-4-carboxamide(Intermediate B, 50 mg, 0.18 mmol) in acetonitrile (0.75 mL) and DMEF(0.75 mL) was added potassium carbonate (31 mg, 0.23 mmol) andiodomethane (107 mg, 0.754 mmol). The reaction mixture was stirred at60° C. for 16 h under a nitrogen atmosphere. The mixture wasconcentrated in vacuo. Then, o-tolylboronic acid (41 mg, 0.30 mmol),dioxane (1.0 mL), water (0.2 mL), K₃PO₄.H₂O (89 mg, 0.38 mmol),(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (8.1 mg, 0.0090 mmol) and2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (4.4 mg, 0.0090mmol) were added to the mixture. The mixture was stirred at 70° C. for 3h under a nitrogen atmosphere. The crude residue was diluted indichloromethane (5 mL), dried over anhydrous MgSO₄, filtered throughcelite and concentrated in vaco. The mixture obtained was purified byreverse phase chromatography (acetonitrile 30-70%/0.1% ammoniumhydroxide in water) to give the title compound (37 mg, 69%) as a whitesolid. ¹HNMR (400 MHz, DMSO-d₆)₆δ 7.32 (d, J=2.3 Hz, 1H), 7.29-7.12 (m,5H), 6.95 (d, J=8.3 Hz, 1H), 6.38 (q, J=4.4 Hz, 1H), 4.36 (s, 2H),3.59-3.51 (m, 2H), 3.01-2.94 (m, 2H), 2.88 (s, 3H), 2.53 (d, J=4.3 Hz,3H), 2.26 (s, 3H). LCMS M/Z (M+H) 310.

Example 867-[2-(4-methoxyphenyl)imidazo[1,2-a]pyridin-5-yl]-N-methyl-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxamide

Step 1 5-bromo-2-(4-methoxyphenyl)imidazo[1,2-a]pyridine

To a solution of 6-bromopyridin-2-amine (500 mg, 2.89 mmol) in2-propanol (5.8 mL) was added 2-bromo-1-(4-methoxyphenyl)ethanone (794mg, 3.47 mmol). The mixture was stirred at 80° C. for 20 h. The reactionmixture was then cooled to room temperature and concentrated in vacuo.The crude residue was partitioned between DCM (50 mL) and saturatedaqueous NaHCO₃ solution (50 mL) and the two phases were separated. Theaqueous layer was extracted with DCM (2×50 mL). The combined organiclayers were dried over anhydrous MgSO₄, filtered and concentrated invacuo. The mixture obtained was purified by silica gel chromatography(iPrOAc/Heptane=2:8) to give the title compound (112 mg, 50% purity) asan orange solid that required no further purification for the next step.LCMS M/Z (M+H) 303.

Step 27-[2-(4-methoxyphenyl)imidazo[1,2-a]pyridin-5-yl]-N-methyl-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxamide

To a solution of7-bromo-N-methyl-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxamide(Intermediate A, 50 mg, 0.17 mmol) and bis(pinacolato)diboron (89 mg,0.35 mmol) in dioxane (0.88 mL) was added KOAc (52 mg, 0.53 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(4.2 mg, 0.0053 mmol) and2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (5.1 mg, 0.010mmol). The mixture was stirred at 80° C. for 16 h under a nitrogenatmosphere. The reaction mixture was cooled to room temperature and5-bromo-2-(4-methoxyphenyl)imidazo[1,2-a]pyridine (36 mg, 0.12 mmol),K₃PO₄.H₂O (71 mg, 0.30 mmol), water (0.3 mL), dioxane (0.5 mL) andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(4.2 mg, 0.0053 mmol) were added. The reaction mixture was stirred at70° C. for 5 h under a nitrogen atmosphere. The reaction mixture wasthen cooled to room temperature and concentrated in vacuo. The cruderesidue was diluted in dichloromethane (5 mL), dried over anhydrousMgSO₄, filtered through celite and concentrated in vacuo. The mixtureobtained was purified by reverse phase chromatography (acetonitrile20-60%/0.1% ammonium hydroxide in water) to give the title compound (7.8mg, 10%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.19 (s, 1H),7.99-7.89 (m, 2H), 7.84 (d, J=2.4 Hz, 1H), 7.58 (dd, J=8.1, 1.9 Hz, 2H),7.34 (dd, J=9.0, 7.0 Hz, 1H), 7.18 (d, J=8.3 Hz, 1H), 7.01-6.93 (m, 2H),6.86 (dd, J=7.0, 1.2 Hz, 1H), 6.59-6.48 (m, 1H), 4.55 (s, 2H), 4.12 (dd,J=5.5, 3.3 Hz, 2H), 3.83-3.74 (m, 5H), 2.56 (d, J=4.3 Hz, 3H). LCMS M/Z(M+H) 429.

Example 871-[6-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-3,4-dihydro-2H-quinolin-1-yl]ethanone

Step 1 1-(3,4-dihydro-2H-quinolin-1-yl)ethanone

To a solution of 1,2,3,4-tetrahydroquinoline (2.00 g, 15.0 mmol) in DCM(30 mL) at 0° C. was added TEA (3.14 mL, 22.5 mmol), and aceticanhydride (1.70 mL, 18.0 mmol). The mixture was heated to 32° C. for 2h. The reaction mixture warmed to room temperature and stirred for 2.5h. Water (50 mL) was added and the mixture was extracted with DCM (50mL×2). The combined organic layers were washed with brine (30 mL), driedover anhydrous Na₂SO₄ and then concentrated in under reduced pressure.The residue was purified by silica gel chromatography (100% Heptanes to50% EtOAc in Heptanes gradient) to afford the title compound (2.32 g,88%) as a pale yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 7.26-7.05 (m,4H), 3.81 (t, J=6.6 Hz, 2H), 2.73 (t, J=6.7 Hz, 2H), 2.24 (s, 3H), 1.97(p, J=6.6 Hz, 2H).

Step 2 1-(6-bromo-3,4-dihydro-2H-quinolin-1-yl)ethanone

To a solution of 1-(3,4-dihydro-2H-quinolin-1-yl)ethanone (400 mg, 2.0mmol) in DCM (10 mL) at 0° C. was added N-bromosuccinimide (400 mg, 2.0mmol) portionwise. The mixture was stirred at room temperature for 2 h,then heated at 45° C. for 14 h. After cooling to room temperature, thereaction was concentrated under reduced pressure. The residue waspurified by silica gel chromatography (100% Heptanes to 60% EtOAc inHeptanes gradient) to afford the title compound (0.542 g, 90%) as ayellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.40-7.03 (m, 3H), 3.76 (t, J=6.5Hz, 2H), 2.71 (t, J=6.6 Hz, 2H), 2.22 (s, 3H), 2.04-1.86 (m, 2H).

Step 31-[6-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-3,4-dihydro-2H-quinolin-1-yl]ethanone

To a vial was added7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydroquinoline(Intermediate C, 70.0 mg, 0.266 mmol), methyl4-bromoquinoline-6-carboxylate (243 mg, 0.912 mmol),dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)(33.3 mg, 0.0399 mmol), t-BuONa (51.1 mg, 0.532 mmol) and 1,4-dioxane(0.53 mL). The mixture was sparged with an argon balloon, and thenheated to 120° C. for 16 h under an argon atmosphere. After cooling thereaction to room temperature, DCM (3 mL) was added and the reaction wasfiltered through celite and concentrated under reduced pressure. Thecrude residue was purified by reverse phase chromatography (acetonitrile30-70%/0.1% ammonium hydroxide in water) to give the title compound(40.5 mg, 32%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆, 330 K) δ 7.72(s, 1H), 7.53 (s, 1H), 7.48 (d, J=0.8 Hz, 1H), 7.13-7.02 (m, 3H),6.87-6.60 (m, 2H), 3.86 (s, 3H), 3.73-3.67 (m, 2H), 3.62-3.55 (m, 2H),2.83 (t, J=6.5 Hz, 2H), 2.71 (t, J=6.6 Hz, 2H), 2.18 (s, 3H), 2.03-1.95(m, 2H), 1.93-1.84 (m, 2H). LCMS M/Z (M+H) 437.

Example 886-acetyl-1-methyl-3-[3-(1-methylpyrazol-4-yl)-8-isoquinolyl]-7,8-dihydro-5H-1,6-naphthyridin-2-one

To a vial was added6-acetyl-3-bromo-1-methyl-7,8-dihydro-5H-1,6-naphthyridin-2-one(Intermediate G, 14.6 mg, 0.0512 mmol),3-(1-methylpyrazol-4-yl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline(Intermediate E, 25.7 mg, 0.0768 mmol),2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (1.2 mg, 0.0026mmol),(2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(I)chloride (1.9 mg, 0.0026 mmol), K₃PO₄H₂O (35.4 mg, 0.154 mmol),1,4-dioxane (0.5 mL), and water (0.1 mL). The mixture was sparged withan argon balloon, and then heated to 120° C. for 16 h under an argonatmosphere. After cooling the reaction to room temperature, DCM (3 mL)was added and the reaction was filtered through celite and concentratedunder reduced pressure. The crude residue was purified by reverse phasechromatography (acetonitrile 5-50%/0.1% ammonium hydroxide in water) togive the title compound (16.1 mg, 75%) as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ 8.92 (dt, J=16.1, 0.9 Hz, 1H), 8.32-8.26 (m, 1H), 8.06(q, J=1.3, 0.8 Hz, 2H), 7.87 (d, J=8.3 Hz, 1H), 7.74 (ddd, J=8.3, 7.0,3.6 Hz, 1H), 7.51-7.47 (m, 1H), 7.40 (ddd, J=8.3, 7.0, 1.1 Hz, 1H), 4.48(d, J=17.7 Hz, 2H), 3.91 (s, 3H), 3.78 (t, J=5.9 Hz, 2H), 3.51 (s, 3H),3.02-2.93 (m, 1H), 2.92-2.83 (m, 1H), 2.51-2.07 (m, 3H). LCMS M/Z (M+H)414.

Example 896-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-methyl-indoline-2,3-dione

Step 1 6-bromo-1-methyl-indoline-2,3-dione

To a solution of 6-bromoindoline-2,3-dione (0.504 g, 2.23 mmol) inacetonitrile (11 mL) was added K₂CO₃ (1.23 g, 8.92 mmol) theniodomethane (0.278 mL, 4.46 mmol). The reaction mixture was heated at60° C. for 1.5 h. After cooling to room temperature, water (30 mL) wasadded and the mixture was extracted with DCM (30 mL×3). The combinedorganic layers were washed with brine (30 mL), dried over anhydrousNa₂SO₄ and then concentrated in under reduced pressure to give the titlecompound (0.506 g, 95%) that required no further purification. ¹H NMR(400 MHz, CDCl₃) δ 7.46 (dd, J=7.9, 1.0 Hz, 1H), 7.32-7.28 (m, 1H), 7.08(d, J=1.5 Hz, 1H), 3.25 (d, J=0.6 Hz, 3H).

Step 26-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-methyl-indoline-2,3-dione

To a vial was added7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydroquinoline(Intermediate C, 290 mg, 1.10 mmol), 6-bromo-1-methyl-indoline-2,3-dione(317 mg, 1.32 mmol),(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (147 mg, 0.165 mmol), K₃PO₄ (0.723 g, 3.30 mmol), then2-methyl-2-butanol (7.3 mL). The mixture was sparged with an argonballoon, and then heated to 100° C. for 16 h under an argon atmosphere.After cooling the reaction to room temperature, DCM (3 mL) was added andthe reaction was filtered through celite and concentrated under reducedpressure. The crude residue was purified by reverse phase chromatography(acetonitrile 30-70%/0.1% ammonium hydroxide in water) to give the titlecompound (86.6 mg, 18%) as a red solid. ¹H NMR (400 MHz, DMSO-d₆) δ7.90-7.85 (m, 1H), 7.62 (d, J=0.8 Hz, 1H), 7.51 (s, 1H), 7.45 (d, J=8.4Hz, 1H), 7.36 (d, J=1.3 Hz, 1H), 7.09-6.77 (m, 3H), 3.90 (s, 3H),3.86-3.78 (m, 2H), 3.11 (s, 3H), 2.80 (t, J=6.4 Hz, 2H), 1.99 (t, J=6.2Hz, 2H). LCMS M/Z (M+H) 423.

Example 906-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-methyl-indolin-2-one

A solution of6-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-methyl-indoline-2,3-dione(Example 89, 15 mg, 0.174 mmol) in hydrazine monohydrate (1.0 mL) washeated at 100° C. for 2 h. After cooling to room temperature thereaction was concentrated under reduced pressure. The crude residue waspurified by reverse phase chromatography (acetonitrile 30-70%/0.1%ammonium hydroxide in water) followed by SFC (Pyridyl amide 150×30.0 mmI.D., 5 μm; 0.1% ammonium hydroxide in MeOH 5-60%/supercritical CO₂) togive the title compound (4.3 mg, 60%). ¹H NMR (400 MHz, DMSO-d) S 7.75(d, J=0.8 Hz, 1H), 7.50 (d, J=0.8 Hz, 1H), 7.28 (dd, J=7.8, 1.1 Hz, 1H),7.12 (d, J=1.2 Hz, 1H), 6.93 (d, J=1.9 Hz, 1H), 6.91-6.86 (m, 1H),6.86-6.59 (m, 2H), 3.86 (s, 3H), 3.70-3.59 (m, 2H), 3.55 (d, J=1.1 Hz,2H), 3.09 (s, 3H), 2.85 (t, J=6.3 Hz, 2H), 2.08-1.94 (m, 2H). LCMS M/Z(M+H) 409.

Example 915-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-3-methyl-1,3-benzoxazol-2-one

To a vial was added7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydroquinoline(Intermediate C, 50.0 mg, 0.190 mmol),5-bromo-3-methyl-1,3-benzoxazol-2-one (43.3 mg, 0.190 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (11.0 mg, 0.0190 mmol),chloro[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]palladium(II)(16.9 mg, 0.0190 mg), Cs₂CO₃ (124 mg, 0.380 mmol), then toluene (1.3mL). The mixture was sparged with an argon balloon, and then heated to120° C. for 14 h under an argon atmosphere. After cooling the reactionto room temperature, DCM (3 mL) was added and the reaction was filteredthrough celite and concentrated under reduced pressure.

The crude residue was purified by reverse phase chromatography(acetonitrile 30-70%/0.1% ammonium hydroxide in water) to give the titlecompound (20.7 mg, 27%) as a while solid. ¹H NMR (400 MHz, DMSO-d₆) δ7.78-7.71 (m, 1H), 7.49 (d, J=0.8 Hz, 1H), 7.40-7.36 (m, 1H), 7.27 (d,J=2.2 Hz, 1H), 7.12 (d, J=1.4 Hz, 1H), 7.02 (dd, J=8.5, 2.2 Hz, 1H),6.91-6.58 (m, 2H), 3.86 (s, 3H), 3.64-3.57 (m, 2H), 3.34-3.32 (m, 3H),2.86 (s, 2H), 2.06-1.96 (m, 2H). LCMS M/Z (M+H) 411.

Examples 92 and 93(S)-6-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,3-dimethyl-indolin-2-oneand(R)-6-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,3-dimethyl-indolin-2-one

To a vial was added7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydroquinoline(Intermediate C, 26.8 mg, 0.0634 mmol),6-bromo-1,3-dimethyl-indolin-2-one (119 mg, 0.494 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (28.6 mg, 0.0494 mmol),chloro[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]palladium(II)(43.9 mg, 0.0494 mg), Cs2CO₃ (322 mg, 0.988 mmol), then toluene (3.3mL). The mixture was sparged with an argon balloon, and then heated to120° C. for 14 h under an argon atmosphere. After cooling the reactionto room temperature, DCM (3 mL) was added and the reaction was filteredthrough celite and concentrated under reduced pressure. The cruderesidue was purified by reverse phase chromatography (acetonitrile30-70%/0.1% ammonium hydroxide in water) to give racemic6-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,3-dimethyl-indolin-2-one(26.8 mg, 13%) as a yellow solid that was separated by chiral SFC(Chiralpak AD 150×21.2 mm I.D., 5 μm; 0.1% ammonium hydroxide in MeOH35%/supercritical CO₂) to give(R)-6-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,3-dimethyl-indolin-2-one(Example 92, 4.3 mg, first peak) and(S)-6-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,3-dimethyl-indolin-2-one(Example 93, 4.2 mg, second peak). Absolute configuration wasarbitrarily assigned to each diastereomer. Example 92: ¹H NMR (400 MHz,DMSO-d₆) δ 7.72 (d, J=0.8 Hz, 1H), 7.47 (d, J=0.8 Hz, 1H), 7.23-7.16 (m,2H), 7.08 (s, 1H), 6.98 (dd, J=8.2, 2.0 Hz, 1H), 6.64 (s, 2H), 3.89-3.83(m, J=4.1 Hz, 4H), 3.67-3.56 (m, 2H), 3.37-3.34 (m, 3H), 2.86 (d, J=6.6Hz, 2H), 2.08-1.98 (m, 2H), 1.17 (t, J=7.1 Hz, 3H). LCMS M/Z (M+H)423.2. Example 93: ¹H NMR (400 MHz, DMSO-d₆) δ 7.72 (d, J=0.8 Hz, 1H),7.47 (d, J=0.8 Hz, 1H), 7.23-7.16 (m, 2H), 7.08 (s, 1H), 6.98 (dd,J=8.2, 2.0 Hz, 1H), 6.64 (s, 2H), 3.89-3.83 (m, J=4.1 Hz, 4H), 3.67-3.56(m, 2H), 3.37-3.34 (m, 3H), 2.86 (d, J=6.6 Hz, 2H), 2.08-1.98 (m, 2H),1.17 (t, J=7.1 Hz, 3H). LCMS M/Z (M+H) 423.

Example 941,3-dimethyl-5-(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-1H-benzo[d]imidazol-2(3H)-one

Step 1 5-bromo-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one

To a stirred solution of 5-bromo-H-benzo[d]imidazol-2(3H)-one (1.0 g,4.69 mmol) in THF (10 mL) at 0° C. was added NaH (469 mg, 11.74 mmol,60%) and the mixture was stirred for 30 min. Methyliodide (0.88 mL,14.08 mmol) was added dropwise and the mixture stirred at roomtemperature for an additional 16 h. The mixture was quenched withsaturated NH4Cl (20 mL) and extracted with EtOAc (20 mL×2). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (petroleum ether/EtOAc=5:1) to give the title compound(630 mg, 56%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.23 (d, J=8.4Hz, 1H), 7.12 (d, J=2.0 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 3.41 (s, 6H).

Step 21,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one

To a solution of 5-bromo-1,3-dimethyl-H-benzo[d]imidazol-2(3H)-one (100mg, 0.41 mmol) in dioxane (4 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30 mg, 0.04mmol), KOAc (122 mg, 1.24 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (211 mg,0.83 mmol). The mixture was heated to 90° C. for 1 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the reactionmixture was used to the next step directly without further purification.LCMS M/Z (M+H) 289.

Step 31,3-dimethyl-5-(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-1H-benzo[d]imidazol-2(3H)-one

To the above step cooled solution was added8-chloro-3-(1-methyl-H-pyrazol-4-yl)isoquinoline (Intermediate D, 89 mg,0.36 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (17mg, 0.035 mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (27 mg, 0.035 mmol), Na₂CO₃ (110 mg, 1.04 mmol),1,4-dioxane (1 mL) and water (1 mL). The reaction mixture was heated to90° C. for 3 h under a nitrogen atmosphere. After cooling to roomtemperature, the mixture was filtered and concentrated in vacuo. DCM (30mL) was added and washed with water (30 mL×2). The organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude residue was purified by reverse phase chromatography (acetonitrile37-47%/0.05% NH₄OH in water) to give the title compound (14 mg, 9%) as ayellow solid. H NMR (400 MHz, CDCl₃) δ 9.32 (s, 1H), 8.07 (s, 1H), 8.03(s, 1H), 7.85 (s, 1H), 7.82-7.76 (m, 1H), 7.66-7.44 (m, 1H), 7.47 (d,J=6.8 Hz, 1H), 7.29-7.26 (m, 1H), 7.15 (s, 1H) 7.11 (d, J=8.0 Hz, 1H),3.99 (s, 3H), 3.52 (s, 3H), 3.47 (s, 3H). LCMS M/Z (M+H) 370.

Example 951,3-dimethyl-5-(4-methyl-6-(1-methyl-1H-pyrazol-4-yl)-7-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl)-1H-benzo[d]imidazol-2(3H)-one

Step 12-((5-bromo-2-nitro-4-(trifluoromethyl)phenyl)(methyl)amino)ethanol

To a solution of 1-bromo-5-fluoro-4-nitro-2-(trifluoromethyl)benzene(7.0 g, 24.3 mmol) in DMF (50 mL) was added N,N-diisopropylethylamine(12.9 mL, 72.9 mmol) and 2-(methylamino)ethanol (2.2 g, 29.2 mmol). Themixture was heated to 80° C. for 16 h. After cooling the reaction toroom temperature, water (50 mL) was added and extracted with EtOAc (50mL×3). The combined organic layers were washed with brine (50 mL×3),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude residue was purified by silica gel chromatography (petroleumether/EtOAc=3:1) to give the title compound (7.5 g, 90%) as a yellowsolid.

Step 25-bromo-N-(2-chloroethyl)-N-methyl-2-nitro-4-(trifluoromethyl)aniline

To a solution of2-((5-bromo-2-nitro-4-(trifluoromethyl)phenyl)(methyl)amino)ethanol (4g, 11.7 mmol) and pyridine (0.94 mL, 11.7 mmol) in DCM (40 mL) at 0° C.was added thionylchloride (1.7 mL, 23.3 mmol) dropwise. The mixture wasstirred at room temperature for 16 h. DCM (50 mL) was added, washed withsat. aq. NaHCO₃(50 mL×3), brine (50 mL×2). The organic layer was driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The cruderesidue was purified by silica gel chromatography (petroleumether/EtOAc=3:1) to give the title compound (2.7 g, 64%) as yellow oil.

Step 35-bromo-N-(2-chloroethyl)-N¹-methyl-4-(trifluoromethyl)benzene-1,2-diamine

To a solution of5-bromo-N-(2-chloroethyl)-N-methyl-2-nitro-4-(trifluoromethyl)aniline(2.7 g, 7.5 mmol) in AcOH (20 mL) was added Fe powder (2.1 g, 37.3mmol). The mixture was stirred at room temperature for 1 h. Insolublesolid was filtered off, the filtrate was adjusted to pH=8 by adding sat.aq. NaHCO₃ and extracted with EtOAc (50 mL×3). The combined organiclayers were washed with brine (50 mL×3), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo to give the title compound (2.2 g,crude) as a brown solid that required no further purification. LCMS M/Z(M+H) 333.

Step 47-bromo-1-methyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoxaline

To a solution of5-bromo-N-(2-chloroethyl)-N-methyl-4-(trifluoromethyl)benzene-1,2-diamine(2.0 g, 6.0 mmol) in DMF (20 mL) was added potassium iodide (2.0 g, 12.1mmol) and potassium carbonate (2.5 g, 18.1 mmol). The mixture was heatedto 80° C. for 3 h. After cooling the reaction to room temperature, water(50 mL) was added and extracted with EtOAc (50 mL×3). The combinedorganic layers were washed with brine (100 mL×2), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The crude residue waspurified by silica gel chromatography (petroleum ether/EtOAc=3:1) togive the title compound (830 mg, 47%) as a light yellow solid. ¹H NMR(400 MHz, DMSO-d₆) δ 6.72 (s, 1H), 6.63 (s 1H), 6.07 (s, 1H), 3.29-3.26(m, 2H), 3.24-3.21 (m, 2H), 2.83 (s, 3H).

Step 51-methyl-7-(1-methyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoxaline

To a solution of7-bromo-1-methyl-6-(trifluoromethy)-1,2,3,4-tetrahydroquinoxaline (830mg, 2.8 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(702 mg, 3.4 mmol) and sodium carbonate (894 mg, 8.4 mmol) in THF (10mL) and water (2 mL) was addedchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (221 mg, 0.28 mmol) and2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (134 mg, 0.28mmol). The mixture was heated to 60° C. for 16 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the mixturewas filtered and concentrated in vacuo. The crude residue was purifiedby silica gel chromatography (petroleum ether/EtOAc=1:1) to give thetitle compound (383 mg, 46%) as a brown solid. LCMS M/Z (M+H) 297.

Step 61,3-dimethyl-5-(4-methyl-6-(1-methyl-1H-pyrazol-4-yl)-7-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl)-1H-benzo[d]imidazol-2(3H)-one

To a solution of1-methyl-7-(1-methyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoxaline(246 mg, 0.83 mmol), 5-bromo-1,3-dimethyl-H-benzo[d]imidazol-2(3H)-one(200 mg, 0.83 mmol) and K₃PO₄ (528 mg, 2.49 mmol) in 2-methyl-2-butanol(6 mL) was addedmethanesulfonato(2-dicyclohexylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)(70 mg, 0.083 mmol). The mixture was heated to 95° C. for 16 h under anitrogen atmosphere. After cooling the reaction to room temperature, themixture was filtered and concentrated in vacuo. The crude residue waspurified by reverse phase chromatography (acetonitrile 30-60%/0.2%formic acid in water) to give the title compound (63 mg, 17%) as ayellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.56 (s, 1H), 7.43 (s, 1H),7.00-6.90 (m, 2H), 6.87 (s, 1H), 6.78 (s, 1H), 6.55 (s, 1H), 3.95 (s,3H), 3.77-3.75 (m, 2H), 3.50-3.47 (m, 2H) 3.45 (s, 3H), 3.41 (s, 3H),3.00 (s, 3H). LCMS M/Z (M+H) 457.

Example 966-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4-isopropyl-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one

Step 16-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,3-dimethyl-4-(prop-1-en-2-yl)-1H-benzo[d]imidazol-2(3H)-one

To a solution of4-chloro-6-(7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one(Example 33, 100 mg, 0.22 mmol) in THF (8 mL) and water (2 mL) was added2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (9 mg, 0.02mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (16 mg, 0.02 mmol), Cs₂CO₃ (213 mg, 0.66 mmol) and4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (44 mg, 0.26mmol). The mixture was heated to 100° C. for 16 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the mixturewas filtered and concentrated in vacuo. The crude residue was purifiedby silica gel chromatography (petroleum ether/EtOAc=3:2) to give thetitle compound (90 mg, 89%) as colorless oil. LCMS M/Z (M+H) 464.

Step 26-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4-isopropyl-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one

To a solution of6-(7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,3-dimethyl-4-(prop-1-en-2-yl)-1H-benzo[d]imidazol-2(3H)-one(90 mg, 0.19 mmol) in MeOH (10 mL) was added 10% Pd/C (100 mg). Themixture was stirred at room temperature for 16 h under a hydrogenatmosphere (15 Psi). The mixture was filtered and the filtrate wasconcentrated in vacuo. The crude residue was purified by silica gelchromatography (EtOAc) to give the title compound (34 mg, 37%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.73 (s, 1H), 7.48 (s, 1H),7.08 (s, 1H), 6.97 (d, J=2.0 Hz, 1H), 6.91 (d, J=2.0 Hz, 1H), 6.73 (s,1H), 6.72 (t, J=55.2 Hz, 1H), 3.86 (s, 3H), 3.63-3.61 (m, 3H), 3.58 (s,3H), 3.30 (s, 3H), 2.86 (t, J=5.6 Hz, 2H), 2.05-2.00 (m, 2H), 1.24 (d,J=6.4 Hz, 6H). LCMS M/Z (M+H) 466.

Example 976-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,3-dimethyl-4-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-2(3H)-one

Step 16-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4-(3,6-dihydro-2H-pyran-4-yl)-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one

To a solution of4-chloro-6-(7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one(Example 33,200 mg, 0.44 mmol) in THF (5 mL) and water (1 mL) was added2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (21 mg, 0.044mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (34 mg, 0.044 mmol), Na₂CO₃ (139 mg, 1.31 mmol) and2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(110 mg, 0.53 mmol). The mixture was heated to 100° C. for 12 h under anitrogen atmosphere. After cooling the reaction to room temperature, themixture was filtered and concentrated in vacuo. The crude residue waspurified by silica gel chromatography (petroleum ether/EtOAc=1:1) togive the title compound (110 mg, 50%) as light yellow oil. LCMS M/Z(M+H) 506.

Step 26-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,3-dimethyl-4-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-2(3H)-one

To a solution of6-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4-(3,6-dihydro-2H-pyran-4-yl)-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one(45 mg, 0.09 mmol) in EtOH (10 mL) was added Pd(OH)₂ (62 mg). Themixture was stirred at room temperature for 12 h under a hydrogenatmosphere (15 psi). The mixture was filtered and concentrated in vacuo.The crude residue was purified by reverse phase chromatography(acetonitrile 40-70%/0.05% NH₄OH in water) to give the title compound (8mg, 18%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.73 (s, 1H),7.48 (s, 1H), 7.09 (s, 1H), 6.99 (d, J=1.2 Hz, 1H), 6.86 (s, 1H), 6.73(t, J=55.2 Hz, 1H), 6.72, (s, 1H), 3.93-3.90 (m, 2H), 3.86 (s, 3H),3.64-3.62 (m, 1H), 3.61 (s, 3H), 3.53-3.48 (m, 4H), 3.30 (s, 3H),2.88-2.84 (m, 2H), 2.03-2.01 (m, 2H), 1.75-1.65 (m, 4H). LCMS M/Z (M+H)508.

Example 986-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,3-dimethyl-4-(1-oxido-3,6-dihydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2(3H)-one

Step 16-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4-(3,6-dihydro-2H-thiopyran-4-yl)-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one

To a solution of4-chloro-6-(7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one(Example 33, 500 mg, 1.09 mmol) in THF (10 mL) and water (2 mL) wasadded 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (52 mg,0.11 mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (43 mg, 0.05 mmol), Na₂CO₃ (347 mg, 3.28 mmol) and2-(3,6-dihydro-2H-thiopyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(59 mg, 0.26 mmol). The mixture was heated to 80° C. for 16 h under anitrogen atmosphere. After cooling the reaction to room temperature,water (50 mL) was added and extracted with EtOAc (30 mL×3). The combinedorganic layers were washed with brine (30 mL×2), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The crude residue waspurified by Prep-TLC (DCM/MeOH=20:1) to give the title compound (320 mg,56%) as a white solid. LCMS M/Z (M+H) 522.

Step 26-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,3-dimethyl-4-(1-oxido-3,6-dihydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2(3H)-one

To a solution of6-(7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4-(3,6-dihydro-2H-thiopyran-4-yl)-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one(100 mg, 0.19 mmol) in THF (5 mL) and water (1 mL) at 0° C. was addedoxone (59 mg, 0.1 mmol) portionwise. The mixture was stirred at 25° C.for 2 h. The reaction was quenched by sat. aq. Na₂SO₃ (5 mL) andextracted with EtOAc (30 mL×3). The combined organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The cruderesidue was purified by Prep-TLC (DCM/MeOH=20:1) to give the titlecompound (40 mg, 36%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 9.54(s, 1H), 7.41 (s, 1H), 7.06 (s, 1H), 6.90 (s, 1H), 6.84 (s, 1H), 6.79(s, 1H), 6.48 (t, J=55.6 Hz, 1H), 5.73-5.69 (m, 1H), 3.96 (s, 3H),3.67-3.64 (m, 2H), 3.51 (s, 3H), 3.40 (s, 3H), 3.28-3.25 (m, 1H),3.11-2.91 (m, 5H), 2.65-2.61 (m, 2H), 2.12-2.10 (m, 2H). LCMS M/Z (M+H)538.

Example 996-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,3-dimethyl-4-propyl-1H-benzo[d]imidazol-2(3H)-one

To a solution of4-chloro-6-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one(Example 33, 100 mg, 0.22 mmol) in toluene (4 mL) and water (0.4 mL) wasadded potassium isopropyltrifluoroborate (49 mg, 0.33 mmol),chloro[(di(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II)(15 mg, 0.022 mmol) and Cs₂CO₃ (213 mg, 0.66 mmol). The mixture washeated to 100° C. for 16 h under a nitrogen atmosphere. After coolingthe reaction to room temperature, EtOAc (20 mL) was added and washedwith water (20 mL×3) and brine (20 mL). The organic phase was dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude residuewas purified by reverse phase chromatography (acetonitrile 38-68%/0.2%formic acid in water) to give the title compound (1 mg, 1%) as a whitesolid. H NMR (400 MHz, DMSO-d₆) δ 7.72 (s, 1H), 7.47 (s, 1H), 7.07 (s,1H), 6.98 (d, J=1.6 Hz, 1H), 6.76 (d, J=1.6 Hz, 1H), 6.71 (t, J=55.6 Hz,1H), 6.66 (s, 1H), 3.86 (s, 3H), 3.60-3.58 (m, 2H), 3.55 (s, 3H), 3.30(s, 3H), 2.86-2.85 (m, 4H), 2.02-1.99 (m, 2H), 1.63-1.58 (m, 2H), 0.93(t, J=6.8 Hz, 3H). LCMS M/Z (M+H) 466.

Example 1006-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4-methoxy-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one

To a solution of4-chloro-6-(7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one(Example 33, 100 mg, 0.22 mmol) in 1,4-dioxane (4 mL) was added methanol(0.044 mL, 1.09 mmol),methanesulfonato(2-(di-t-butylphosphino)-3-methoxy-6-methyl-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)(37 mg, 0.044 mmol) and t-BuONa (29 mg, 0.31 mmol). The mixture washeated to 100° C. for 20 h under a nitrogen atmosphere. After cooling toroom temperature, the mixture was filtered and concentrated in vacuo.The crude residue was purified by reverse phase chromatography(acetonitrile 38-68%/0.05% NH₄OH in water) to give the title compound(13 mg, 13%) as a white solid. H NMR (400 MHz, DMSO-d₆) δ 7.73 (s, 1H),7.48 (s, 1H), 7.09 (s, 1H), 6.80 (s, 1H), 6.73 (t, J=55.2 Hz, 1H),6.68-6.67 (m, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 3.62-3.59 (m, 2H), 3.51(s, 3H), 3.27 (s, 3H), 2.86 (t, J=5.6 Hz, 2H), 2.03-2.01 (m, 2H). LCMSM/Z (M+H) 454.

Example 1016-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4-ethynyl-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one

Step 16-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,3-dimethyl-4-((triisopropylsilyl)ethynyl)-1H-benzo[d]imidazol-2(3H)-one

To a solution of4-chloro-6-(7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one(Example 33, 100 mg, 0.22 mmol) in MeCN (5 mL) was addedbis(acetonitrile)dichloropalladium(II) (6 mg, 0.022 mmol),2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (10 mg, 0.022mmol), ethynyltriisopropylsilane (0.13 mL, 0.66 mmol) and Cs₂CO₃ (213mg, 0.66 mmol). The mixture was heated to 90° C. for 15 h under anitrogen atmosphere. After cooling the reaction to room temperature,EtOAc (50 mL) was added and washed with water (30 mL) and brine (30 mL).The organic phase was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (petroleum ether/EtOAc=2:1) to give the title compound(70 mg, 53%) as a white solid. LCMS M/Z (M+H) 604.

Step 26-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4-ethynyl-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one

To a solution of6-(7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,3-dimethyl-4-((triisopropylsilyl)ethynyl)-1H-benzo[d]imidazol-2(3H)-one(70 mg, 0.11 mmol) in THF (2 mL) was added TBAF (0.2 mL, 0.2 mmol, 1 Min THF). The reaction was stirred at room temperature for 12 h. Thereaction mixture was concentrated in vacuo. The crude residue wasdissolved in DCM (25 mL), washed with water (20 mL×2) and brine (20 mL).The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by Prep-TLC(petroleum ether/EtOAc=1:1) to give the title compound (10 mg, 19%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.74 (s, 1H), 7.49 (s, 1H),7.23-7.22 (m, 1H), 7.11 (s, 1H), 7.01-7.00 (m, 1H), 6.74 (t, J=54.8 Hz,1H), 6.61 (s, 1H), 4.49 (s, 1H), 3.86 (s, 3H), 3.63 (s, 3H), 3.60-3.56(m, 2H), 3.31 (s, 3H), 2.87-2.84 (m, 2H), 2.02-2.00 (m, 2H). LCMS M/Z(M+H) 448.

Example 1025-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-ethynyl-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one

Step 15-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,3-dimethyl-6-((triisopropylsilyl)ethynyl)-1H-benzo[d]imidazol-2(3H)-one

To a solution of5-chloro-6-(7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one(Example 46,150 mg, 0.33 mmol) in DMF (5 mL) was addedbis[dicyclohexyl(2;,4;,6;-triisopropyl-[1,1′:3′,1″-terphenyl]-2-1-yl)phosphane]palladium(II)dichloride (42 mg, 0.03 mmol), ethynyltriisopropylsilane (0.19 mL, 0.98mmol) and NaHCO₃(83 mg, 0.98 mmol). The mixture was heated to 120° C.for 15 h under a nitrogen atmosphere. After cooling the reaction to roomtemperature, DCM (20 mL) was added and washed with water (10 mL) andbrine (10 mL). The organic phase was dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The crude residue was purified bysilica gel chromatography (petroleum ether/EtOAc=10:1) to give the titlecompound (100 mg, 51%) as yellow oil. LCMS M/Z (M+H) 604.

Step 25-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-ethynyl-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one

To a solution of5-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,3-dimethyl-6-((triisopropylsilyl)ethynyl)-1H-benzo[d]imidazol-2(3H)-one(100 mg, 0.17 mmol) in THF (4 mL) was added TBAF (0.33 mL, 0.33 mmol, 1M in THF). The reaction was stirred at room temperature for 12 h. Thereaction mixture was concentrated in vacuo. The crude residue wasdissolved in DCM (20 mL), washed with water (20 mL×3) and brine (20 mL).The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by Prep-TLC(petroleum ether/EtOAc=1:1) to give the title compound (12 mg, 17%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.71 (s, 1H), 7.47 (s, 1H),7.42 (s, 1H), 7.22 (s, 1H), 7.06 (s, 1H), 6.69 (t, J=55.2 Hz, 1H), 6.25(s, 1H), 4.08 (s, 1H), 3.85 (s, 3H), 3.59-3.55 (m, 2H), 3.36 (s, 3H),3.31 (s, 3H), 2.88-2.84 (m, 2H), 2.06-2.02 (m, 2H). LCMS M/Z (M+H) 448.

Example 103N,1-dimethyl-3-(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide

Step 1 methyl1-methyl-3-(3-(1-methyl-H-pyrazol-4-yl)isoquinolin-8-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate

To a solution of methyl 1-methyl-2-oxo-3H-benzimidazole-5-carboxylate(200 mg, 0.96 mmol) in DCM (10 mL) was added(3-(1-methyl-H-pyrazol-4-yl)isoquinolin-8-yl)boronic acid (IntermediateF, 368 mg, 1.46 mmol), pyridine-n-oxide (276 mg, 2.9 mmol), pyridine(1.0 mL, 9.6 mmol) and copper(II) acetate (528 mg, 2.9 mmol). Themixture was stirred at room temperature for 48 h under an oxygentatmosphere. Water (50 mL) was added and extracted with DCM (30 mL×3).The combined organic layers were dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo. The crude residue was purified by Prep-TLC(petroleum ether/EtOAc=2:3) to give the title compound (70 mg, 17%) asyellow oil. LCMS M/Z (M+H) 414.

Step 21-methyl-3-(3-(1-methyl-H-pyrazol-4-yl)isoquinolin-8-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylicacid

To a solution of methyl1-methyl-3-(3-(1-methyl-H-pyrazol-4-yl)isoquinolin-8-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate(70 mg, 0.17 mmol) in MeOH (5 mL) and water (1 mL) was added lithiumhydroxide monohydrate (43 mg, 1.02 mmol). The mixture was heated to 50°C. for 12 h under a nitrogen atmosphere. After cooling the reaction toroom temperature, DCM (50 mL) was added and washed with water (20 mL×2)and brine (10 mL). The organic phase was dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo to give the title compound (55 mg,81%) as a yellow solid that required no further purification. LCMS M/Z(M+H) 400.

Step 3N,1-dimethyl-3-(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide

To a solution of1-methyl-3-(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylicacid (55 mg, 0.14 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.4 mmol)in DMF (2.5 mL) was addedO-(7-azabenzotriazol-1-yl)-N,N,N′,N-tetramethyluroniumhexafluorophosphate (78 mg, 0.21 mmol) and methanamine (0.3 mL, 0.3mmol, 1 M in THF). The reaction was stirred at room temperature for 1 h.EtOAc (30 mL) was added and washed with water (30 mL×3) and brine (30mL). The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by reverse phasechromatography (acetonitrile 46-76%/0.05% NH₄OH in water) to give thetitle compound (6 mg, 10%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆)δ 8.92 (s, 1H), 8.32 (s, 1H), 8.27-8.26 (m, 1H), 8.23 (s, 1H), 8.13-8.06(m, 2H), 7.95-7.91 (m, 1H), 7.78-7.74 (m, 1H), 7.70-7.68 (m, 1H),7.42-7.40 (m, 1H), 7.20 (s, 1H), 3.91 (s, 3H), 3.51 (s, 3H), 2.67 (d,J=4.4 Hz, 3H). LCMS M/Z (M+H) 413.

Example 1045-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N,1,7-trimethyl-1H-indole-3-carboxamide

To a solution of7-chloro-5-(7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N,1-dimethyl-1H-indole-3-carboxamide(Example 54, 100 mg, 0.21 mmol) in toluene (5 mL) and water (0.5 mL) wasadded potassium methyltrifluoroborate (38 mg, 0.31 mmol),chloro[(di(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II)(14 mg, 0.021 mmol 1) and Cs₂CO₃ (202 mg, 0.62 mmol). The mixture washeated to 100° C. for 16 h under a nitrogen atmosphere. After coolingthe reaction to room temperature, EtOAc (20 mL) was added and washedwith water (20 mL×3) and brine (20 mL). The organic phase was dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude residuewas purified by reverse phase chromatography (acetonitrile 43-73%/0.05%NH₄OH in water) to give the title compound (17 mg, 18%) as a whitesolid. H NMR (400 MHz, DMSO-d₆) δ 7.89 (d, J=1.8 Hz, 1H), 7.85-7.80 (m,2H), 7.72 (s, 1H), 7.47 (s, 1H), 7.07 (s, 1H), 6.82 (s, 1H), 6.69 (t,J=55.2 Hz, 1H), 6.51 (s, 1H), 4.08 (s, 3H), 3.85 (s, 3H), 3.57 (t, J=5.6Hz, 2H), 2.89-2.85 (m, 2H), 2.80-2.69 (m, 6H), 2.07-2.01 (m, 2H). LCMSM/Z (M+H) 464.

Example 1055-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N,1-dimethyl-7-(tetrahydro-2H-pyran-4-yl)-1H-indole-3-carboxamide

Step 15-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-7-(3,6-dihydro-2H-pyran-4-yl)-N,1-dimethyl-1H-indole-3-carboxamide

To a solution of4-chloro-6-(7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one(Example 54.77 mg, 0.16 mmol) in 1,4-dioxane (5 mL) and water (1 mL) wasadded 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (8 mg,0.016 mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (13 mg, 0.016 mmol), Na₂CO₃ (51 mg, 0.48 mmol) and2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(50 mg, 0.24 mmol). The mixture was heated to 100° C. for 3 h under anitrogen atmosphere. After cooling the reaction to room temperature, themixture was filtered and concentrated in vacuo. The crude residue waspurified by silica gel chromatography (petroleum ether/EtOAc=1:1) togive the title compound (65 mg, 77%) as light yellow oil. LCMS M/Z (M+H)532.

Step 25-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N,1-dimethyl-7-(tetrahydro-2H-pyran-4-yl)-1H-indole-3-carboxamide

To a solution of5-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-7-(3,6-dihydro-2H-pyran-4-yl)-N,1-dimethyl-1H-indole-3-carboxamide(30 mg, 0.06 mmol) in EtOAc (6 mL) was added platinum(IV) oxide (64 mg).The mixture was stirred at room temperature for 24 h under a hydrogenatmosphere (50 psi). The mixture was filtered and concentrated in vacuo.The crude residue was purified by reverse phase chromatography(acetonitrile 40-70%/0.05% NH₄OH in water) to give the title compound (2mg, 8%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.91-7.89 (m, 1H),7.82-7.79 (m, 2H), 7.70 (s, 1H), 7.45 (s, 1H), 7.05 (s, 1H), 6.97 (s,1H), 6.67 (t, J=55.2 Hz, 1H), 6.60 (s, 1H), 4.05 (s, 3H), 3.92-3.91 (m,2H), 3.83 (s, 3H), 3.61-3.59 (m, 2H), 3.54-3.48 (m, 2H), 2.87-2.83 (m,2H), 2.71 (d, J=4.4 Hz, 3H), 2.03-2.00 (m, 2H), 1.76-1.71 (m, 4H). LCMSM/Z (M+H) 534.

Example 1065-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-7-methoxy-N,1-dimethyl-1H-indole-3-carboxamide

To a solution of7-chloro-5-(7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N,1-dimethyl-1H-indole-3-carboxamide(Example 54, 100 mg, 0.21 mmol) in 1,4-dioxane (4 mL) was added methanol(0.042 mL, 1.09 mmol),methanesulfonato(2-(di-t-butylphosphino)-3-methoxy-6-methyl-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)(35 mg, 0.041 mmol) and t-BuONa (28 mg, 0.29 mmol). The mixture washeated to 100° C. for 20 h under a nitrogen atmosphere. After cooling toroom temperature, the mixture was filtered and concentrated in vacuo.The crude residue was purified by reverse phase chromatography(acetonitrile 43-73%/0.05% NH₄OH in water) to give the title compound(10 mg, 11%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.83-7.78 (m,2H), 7.72 (s, 1H), 7.62 (d, J=1.6 Hz, 1H), 7.47 (s, 1H), 7.08 (s, 1H),6.70 (t, J=55.2 Hz, 1H), 6.64-6.59 (m, 2H), 4.02 (s, 3H), 3.86 (s, 3H),3.85 (s, 3H), 3.61 (t, J=5.2 Hz, 2H), 2.89-2.86 (m, 2H), 2.73 (d, J=4.4Hz, 3H), 2.08-2.00 (m, 2H). LCMS M/Z (M+H) 480.

Example 1075-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-(2H)-yl)-N,1-dimethyl-7-(prop-1-en-2-yl)-1H-indole-3-carboxamide

Step 1 methyl5-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-methyl-7-(prop-1-en-2-yl)-1H-indole-3-carboxylate

To a solution of methyl7-chloro-5-(7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-methyl-1H-indole-3-carboxylate(Example 54, 71 mg, 0.15 mmol) in 1,4-dioxane (5 mL) and water (1 mL)was added 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (7 mg,0.015 mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (12 mg, 0.015 mmol), Na₂CO₃ (47 mg, 044 mmol) and4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (37 mg, 0.22mmol). The mixture was heated to 90° C. for 12 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the mixturewas filtered and concentrated in vacuo. The crude residue was purifiedby silica gel chromatography (petroleum ether/EtOAc=1:1) to give thetitle compound (70 mg, 98%) as light yellow oil. LCMS M/Z (M+H) 491.

Step 25-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-methyl-7-(prop-1-en-2-yl)-1H-indole-3-carboxylicacid

To a solution of methyl5-(7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-methyl-7-(prop-1-en-2-yl)-1H-indole-3-carboxylate(70 mg, 0.14 mmol) in MeOH (2 mL) and water (0.4 mL) was added lithiumhydroxide monohydrate (60 mg, 1.43 mmol). The mixture was heated to 50°C. for 12 h under a nitrogen atmosphere. After cooling the reaction toroom temperature, the mixture was concentrated in vacuo. Water (10 mL)was added and the mixture was acidified with HCl (2 N) to pH 4 and thenextracted with DCM (20 mL×3). The combined organic layers were washedwith brine (20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (70 mg, crude) ascolorless oil that required no further purification. LCMS M/Z (M+H) 477.

Step 35-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N,1-dimethyl-7-(prop-1-en-2-yl)-1H-indole-3-carboxamide

To a solution of5-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-methyl-7-(prop-1-en-2-yl)-1H-indole-3-carboxylicacid (70 mg, 0.15 mmol) and N,N-diisopropylethylamine (0.08 mL, 0.44mmol) in DMF (3 mL) was added0-(7-azabenzotriazol-1-yl)-N,N,N′,N-tetramethyluroniumhexafluorophosphate (67 mg, 0.18 mmol) and methylamine hydrochloride (15mg, 0.22 mmol). The reaction was stirred at room temperature for 12 h.EtOAc (30 mL) was added and washed with water (30 mL×3) and brine (30mL). The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by reverse phasechromatography (acetonitrile 30-60%/0.05% NH₄OH in water) to give thetitle compound (6 mg, 8%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ8.01-7.95 (m, 1H), 7.90 (s, 1H), 7.88-7.84 (m, 1H), 7.73 (s, 1H), 7.47(s, 1H), 7.08 (s, 1H), 6.82 (s, 1H), 6.70 (t, J=54.8 Hz, 1H), 6.64 (s,1H), 5.38 (s, 1H), 4.98 (s, 1H), 3.86 (s, 3H), 3.65-3.60 (m, 2H), 3.31(s, 3H), 2.89-2.85 (m, 2H), 2.74 (d, J=4.4 Hz, 3H), 2.15 (s, 3H),2.05-2.01 (m, 2H). LCMS M/Z (M+H) 490.

Example 1085-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-7-isopropyl-N,1-dimethyl-1H-indole-3-carboxamide

To a solution of5-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N,1-dimethyl-7-(prop-1-en-2-yl)-1H-indole-3-carboxamide(Example 107, 40 mg, 0.08 mmol) in MeOH (5 mL) was added 10% Pd/C (30mg). The mixture was stirred at room temperature for 3 h under ahydrogen atmosphere (15 Psi). The mixture was filtered and the filtratewas concentrated in vacuo. The crude residue was purified by reversephase chromatography (acetonitrile 25-55%/0.05% NH₄OH in water) to givethe title compound (6 mg, 16%) as a white solid. H NMR (400 MHz,DMSO-d₆) δ 7.91-7.90 (m, 1H), 7.84-7.81 (m, 2H), 7.72 (s, 1H), 7.47 (s,1H), 7.07 (s, 1H), 7.02-7.01 (m, 1H), 6.69 (t, J=55.6 Hz, 1H), 6.64 (s,1H), 4.06 (s, 3H), 3.86 (s, 3H), 3.85-3.79 (m, 1H), 3.63 (t, J=5.2 Hz,2H), 2.90-2.85 (m, 2H), 2.74 (d, J=4.4 Hz, 3H), 2.05-2.03 (m, 2H), 1.28(d, J=6.8 Hz, 6H). LCMS M/Z (M+H) 492.

Example 1099-ethyl-N-methyl-7-(o-tolyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxamide

Step 1 tert-butyl7-(o-tolyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate

To a solution of tert-butyl 7-bromo-2,3-dihydrobenzo[][1,4]oxazepine-4(5H)-carboxylate (1.0 g, 3.05 mmol),2-methylphenylboronicacid (414 mg, 3.05 mmol) and sodium carbonate (969mg, 9.14 mmol) in THF (20 mL) and water (4 mL) was addedchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (240 mg, 0.30 mmol) and2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (145 mg, 0.30mmol). The mixture was heated to 60° C. for 16 h under a nitrogenatmosphere. After cooling the reaction to room temperature, the mixturewas filtered and concentrated in vacuo. The crude residue was purifiedby silica gel chromatography (petroleum ether/EtOAc=3:1) to give thetitle compound (1.0 g, 97%) as a light yellow solid. LCMS M/Z (M-Boc+H)240.

Step 2 tert-butyl9-chloro-7-(o-tolyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate

To a stirred solution of tert-butyl 7-(o-tolyl)-2,3-dihydrobenzo[][1,4]oxazepine-4(5H)-carboxylate (1 g, 2.95 mmol) in acetonitrile (10mL) at 0° C. was added N-chlorosuccinimide (393 mg, 2.95 mmol)portionwise and then heated to 50° C. for 12 h. After cooling to roomtemperature, the reaction was concentrated in vacuo. EtOAc (100 mL) wasadded and washed with water (100 mL×3), brine (100 mL). The organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The crude residue was purified by silica gel columnchromatography (petroleum ether/EtOAc=20:1) to give the title compound(900 mg, 82%) as yellow oil. ¹H NMR (400 MHz, DMSO-d) 7.33-7.23 (m, 4H),7.17-7.13 (m, 2H), 4.55-4.47 (m, 2H), 4.20-4.10 (m, 2H), 3.76 (s, 2H),2.23 (s, 3H), 1.36-1.30 (m, 9H).

Step 3 9-chloro-7-(o-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine

To a solution of tert-butyl9-chloro-7-(o-tolyl)-2,3-dihydrobenzo[/][1,4]oxazepine-4(5H)-carboxylate(900 mg, 2.41 mmol) in DCM (4 mL) was addded trifluoroacetic acid (2.0mL, 26.31 mmol) dropwise. The reaction mixture was stirred at roomtemperature for 1 h and concentrated in vacuo to give the title compound(780 mg) as light yellow oil that required no further purification.

Step 49-chloro-N-methyl-7-(o-tolyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxamide

To a solution of N-methyl-1H-imidazole-1-carboxamide (1.07 g, 8.55 mmol)in DCM (5 mL) was added9-chloro-7-(o-tolyl)-2,3,4,5-tetrahydrobenzo[/][1,4]oxazepine (780 mg,2.85 mmol) and triethylamine (0.40 mL, 2.85 mmol). The reaction mixturewas stirred at room temperature for 12 h and concentrated in vacuo.EtOAc (100 mL) was added and washed with water (50 mL×3) and brine (30mL). The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by silica gelcolumn chromatography (petroleum ether/EtOAc=3:1) to give the titlecompound (650 mg, 69%) as a yellow solid. LCMS M/Z (M+H) 331.

Step 59-ethyl-N-methyl-7-(o-tolyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxamide

To a solution of9-chloro-N-methyl-7-(o-toly)-2,3-dihydrobenzo[/][1,4]oxazepine-4(5H)-carboxamide(100 mg, 0.22 mmol) in toluene (5 mL) and water (0.50 mL) was addedpotassium ethyltrifluoroborate (45 mg, 0.33 mmol),chloro[(di(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II)(15 mg, 0.02 mmol) and Cs₂CO₃ (213 mg, 0.66 mmol). The mixture washeated to 100° C. for 16 h under a nitrogen atmosphere. After cooling toroom temperature, the reaction was concentrated in vacuo. EtOAc (10 mL)was added and washed with water (5 mL×3) and brine (5 mL). The organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The crude residue was purified by reverse phase chromatography(acetonitrile 30-60%/0.05% NH₄OH in water) to give the title compound(41 mg, 58%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.31-7.15(m, 5H), 7.04 (d, J=2.0 Hz, 1H), 6.52-6.48 (m, 1H), 4.43 (s, 2H),4.02-3.94 (m, 2H), 3.75-3.68 (m, 2H), 2.60 (q, J=7.6 Hz, 2H), 2.52 (s,3H), 2.24 (s, 3H), 1.13 (t, J=7.6 Hz, 3H). LCMS M/Z (M+H) 325.

Example 1109-isopropyl-N-methyl-7-(o-tolyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxamide

Step 1N-methyl-9-(prop-1-en-2-yl)-7-(o-tolyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxamide

To a solution9-chloro-N-methyl-7-(o-toly)-2,3-dihydrobenzo[/][1,4]oxazepine-4(5H)-carboxamide(Example 109, 200 mg, 0.60 mmol),4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (203 mg, 1.21mmol) and K₃PO₄ (385 mg, 1.81 mmol) in 1,4-dioxane (3 mL) and water(0.60 mL) was addeddicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (297 mg,0.73 mmol) and Pd (OAc) (14 mg, 0.06 mmol). The mixture was irradiatedin a microwave at 80° C. for 0.5 h. DCM (10 mL) was added and washedwith water (10 mL×2), brine (10 mL). The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude residuewas purified by silica gel column chromatography (petroleumether/EtOAc=4:1) to give the title compound (130 mg, 64%) as lightyellow oil. LCMS M/Z (M+H) 337.

Step 29-isopropyl-N-methyl-7-(o-tolyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxamide

To a solution ofN-methyl-9-(prop-1-en-2-yl)-7-(o-tolyl)-2,3-dihydrobenzo[][1,4]oxazepine-4(5H)-carboxamide (130 mg, 0.39 mmol) in MeOH (10 mL)was added 10% Pd/C (100 mg). The resulting mixture was purged with ahydrogen atmosphere (15 psi) at room temperature for 16 h. The reactionmixture was filtered and concentrated in vacuo. The crude residue waspurified by reverse phase chromatography (acetonitrile 55-85%/0.05%NH₄OH in water) to give the title compound (48 mg, 36%) as a whitesolid. H NMR (400 MHz, DMSO-d₆) δ 7.29-7.16 (m, 5H), 7.05 (s, 1H),6.48-6.44 (m, 1H), 4.41 (s, 2H), 3.95-3.94 (m, 2H), 3.74-3.70 (m, 2H),3.28-3.24 (m, 1H), 2.51 (s, 3H), 2.22 (s, 3H), 1.15 (d, J=6.8 Hz, 6H).LCMS M/Z (M+H) 339.

Example 1119-methoxy-N-methyl-7-(o-tolyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxamide

Step 1 tert-butyl9-bromo-7-(o-tolyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate

To a stirred solution of tert-butyl 7-(o-tolyl)-2,3-dihydrobenzo[][1,4]oxazepine-4(5H)-carboxylate (Example 109, 100 mg, 0.29 mmol) inacetonitrile (2 mL) at 0° C. was added N-bromosuccinimide (175 mg, 0.88mmol) portionwise and then heated to 50° C. for 12 h. After cooling toroom temperature, the reaction was concentrated in vacuo. EtOAc (30 mL)was added and washed with water (20 mL×3), brine (20 mL). The organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The crude residue was purified by silica gel columnchromatography (petroleum ether/EtOAc=20:1) to give the title compound(70 mg, 57%) as yellow oil.

Step 2 9-bromo-7-(o-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine

To a solution of tert-butyl 9-bromo-7-(o-tolyl)-2,3-dihydrobenzo[][1,4]oxazepine-4(5H)-carboxylate (70 mg, 0.17 mmol) in DCM (2 mL) wasaddded trifluoroacetic acid (1.0 mL, 13.16 mmol) dropwise. The reactionmixture was stirred at room temperature for 1 h and concentrated invacuo to give the title compound (55 mg, crude) as light yellow oil thatrequired no further purification.

Step 39-bromo-N-methyl-7-(o-tolyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxamide

To a solution of N-methyl-1H-imidazole-1-carboxamide (194 mg, 1.55 mmol)in DCM (3 mL) was added9-bromo-7-(o-tolyl)-2,3,4,5-tetrahydrobenzo[/][1,4]oxazepine (55 mg,0.17 mmol) and triethylamine (0.024 mL, 0.17 mmol). The reaction mixturewas stirred at room temperature for 5 h and concentrated in vacuo. DCM(30 mL) was added and washed with water (10 mL×3) and brine (10 mL). Theorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo. The crude residue was purified by reverse phase chromatography(acetonitrile 50-80%/0.05% NH₄OH in water) to give the title compound(14 mg, 22%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.44 (s,1H), 7.38 (s, 1H), 7.31-7.23 (m, 3H), 7.21-7.17 (m, 1H), 6.53-6.52 (m,1H), 4.51 (s, 2H), 4.11-4.06 (m, 2H), 3.79-3.74 (m, 2H), 2.52 (d, J=4.0Hz, 3H), 2.25 (s, 3H). LCMS M/Z (M+H) 375.

Step 49-methoxy-N-methyl-7-(o-tolyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxamide

To a solution of 9-bromo-N-methyl-7-(o-tolyl)-2,3-dihydrobenzo[][1,4]oxazepine-4(5H)-carboxamide (150 mg, 0.40 mmol), MeOH (0.081 mL, 2mmol) and t-BuONa (54 mg, 0.56 mmol) in 1,4-dioxane (4 mL) was addedmethanesulfonato(2-(di-t-butylphosphino)-3-methoxy-6-methyl-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)(67 mg, 0.08 mmol). The mixture was heated to 100° C. for 20 h under anitrogen atmosphere. After cooling to room temperature, the reaction wasconcentrated in vacuo. The crude residue was purified by reverse phasechromatography (acetonitrile 17-47%/0.05% NH₄OH in water) to give thetitle compound (62 mg, 47%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 7.25-7.20 (m, 4H), 6.92 (d, J=1.8 Hz, 1H), 6.82 (d, J=1.8 Hz, 1H),6.48-6.45 (m, 1H), 4.42 (s, 2H), 3.97-3.90 (m, 2H), 3.73 (s, 3H),3.71-3.67 (m, 2H), 2.49 (d, J=6.4 Hz, 3H), 2.23 (s, 3H). LCMS M/Z (M+H)327.

Example 1121-(7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethanone

Step 1 tert-butyl7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate

To a solution of tert-butyl7-bromo-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate (800 mg, 2.44mmol),7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline(Intermediate C, 642 mg, 2.44 mmol) and t-BuONa (586 mg, 6.09 mmol) in1,4-dioxane (6 mL) was addeddichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)(193 mg, 0.24 mmol). The reaction mixture was heated to 120° C. for 16 hunder a nitrogen atmosphere. After cooling to room temperature, themixture was filtered and concentrated in vacuo. The crude residue waspurified by silica gel column chromatography (petroleum ether/EtOAc=3:2)to give the title compound (670 mg, 54%) as a yellow solid. LCMS M/Z(M+H) 511.

Step 27-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine

To a solution of tert-butyl7-(7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-2,3-dihydrobenzo[][1,4]oxazepine-4(5H)-carboxylate (870 mg, 1.7 mmol) in DCM (5 mL) at 0°C. was added trifluoroacetic acid (1.26 mL, 17.04 mmol) dropwise. Thereaction mixture was stirred at room temperature for 1 h andconcentrated in vacuo to give the title compound (600 mg, 86%) as ayellow solid that required no further purification. LCMS M/Z (M+H) 411

Step 31-(7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethanone

To a solution of7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-2,3,4,5-tetrahydrobenzo[][1,4]oxazepine (150 mg, 0.37 mmol) and TEA (0.25 mL, 1.83 mmol) in DCM(3 mL) was added acetic anhydride (0.1 mL, 1.1 mmol) dropwised. Themixture was stirred at room temperature for 10 h. Water (30 mL) wasadded and extracted with DCM (20 mL×2). The combined organic layers weredried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude residue was purified by reverse phase chromatography (acetonitrile37-67%/0.2% formic acid in water) to give the title compound (90 mg,53%) as a white solid. H NMR (400 MHz, DMSO-d) 7.74 (s, 1H), 7.49 (s,1H), 7.31 (d, J=2.2 Hz, 1H), 7.15-7.00 (m, 3H), 6.89-6.58 (m, 2H),4.62-4.48 (m, 2H), 4.19-4.01 (m, 2H), 3.93-3.77 (m, 5H), 3.62-3.50 (m,2H), 2.86-2.82 (m, 2H), 2.07-1.88 (m, 5H). LCMS M/Z (M+Na) 475.

Example 1137-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxamide

To a stirred solution of7-(7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-2,3,4,5-tetrahydrobenzo[][1,4]oxazepine (Example 112, 150 mg, 0.37 mmol) and triethylamine (0.25mL, 1.83 mmol) in DCM (5 mL) was addedN-methyl-1H-imidazole-1-carboxamide (92 mg, 0.74 mmol). The reactionmixture was stirred at room temperature for 16 h and concentrated invacuo. The crude residue was purified by reverse phase chromatography(acetonitrile 35-65%/0.2% formic acid in water) to give the titlecompound (83 mg, 48%) as a white solid. H NMR (400 MHz, DMSO-d₆) δ 7.74(s, 1H), 7.49 (s, 1H), 7.31 (d, J=2.2 Hz, 1H), 7.13-7.04 (m, 2H),7.03-6.96 (m, 1H), 6.90-6.59 (m, 2H), 6.48-6.43 (m, 1H), 4.42 (s, 2H),4.01-3.98 (m, 2H), 3.86 (s, 3H), 3.72-3.69 (m, 2H), 3.59-3.51 (m, 2H),2.88-2.79 (m, 2H), 2.52 (s, 3H), 2.03-1.92 (m, 2H). LCMS M/Z (M+Na) 490.

Example 1147-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxamide

Step 1 4-bromo-2-(((2-hydroxypropyl)amino)methyl)phenol

To a stirred solution of 1-aminopropan-2-ol (1.87 g, 24.87 mmol) in MeOH(6 mL) was added 5-bromo-2-hydroxybenzaldehyde (5.0 g, 24.87 mmol).After stirring at room temperature for 2 h, sodium borohydride (0.38 g,9.95 mmol) was added portionwise with vigorous stirring. The mixture wasstirred at room temperature for an additional 30 min. The reactionmixture was used to the next step directly without further purification.LCMS M/Z (M+H) 260.

Step 2 tert-butyl 5-bromo-2-hydroxybenzyl(2-hydroxypropyl)carbamate

To the above step solution was added MeOH (24 mL), NaOH (3.32 g, 83.03mmol) in water (15 mL) and di-tert-butyl dicarbonate (9.0 g, 30.58mmol). After stirring at room temperature for 2 h, additionaldi-tert-butyl dicarbonate (1.07 g, 4.90 mmol) was added. The reactionmixture was stirred room temperature for an additional 12 h andconcentrated in vacuo. Water (5 mL) was added and the mixture wasacidified with HCl (1 N) to pH 5 and then extracted with DCM (30 mL).The organic layer was washed with water (10 mL×2), brine (10 mL), driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo to give thetitle compound (6 g, 72%) as colorless oil that required no furtherpurification. LCMS M/Z (M-Boc) 260.

Step 3 tert-butyl7-bromo-2-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate

To a solution of tert-butyl5-bromo-2-hydroxybenzyl(2-hydroxypropyl)carbamate (2.2 g, 6.11 mmol) andtriphenylphosphine (3.20 g, 12.21 mmol) in THF (15 mL) at 0° C. wasadded DIAD (2.47 g, 12.21 mmol) slowly. The reaction mixture was heatedto 70° C. for 16 h. After cooling to room temperature, the reaction wasdiluted with water (20 mL) and extracted with EtOAc (20 mL). The organiclayer was washed with HCl (1 N, 20 mL), NaOH (1 N, 20 mL), brine (20mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo Thecrude residue was purified by silica gel column chromatography(petroleum ether/EtOAc=9:1) to give the title compound (1.3 g, 62%) as awhite solid. LCMS M/Z (M+H) 342.

Step 4 tert-butyl7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-2-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate

To a solution of tert-butyl 7-bromo-2-methyl-2,3-dihydrobenzo[][1,4]oxazepine-4(5H)-carboxylate (200 mg, 0.58 mmol) and7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline(Intermediate C, 185 mg, 0.70 mmol) in 1,4-dioxane (6 mL) was addeddichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)(46 mg, 0.06 mmol) and t-BuONa (168 mg, 1.75 mmol). The mixture washeated to 120° C. for 16 h under an argon atmosphere. After cooling thereaction to room temperature, the mixture was filtered and concentratedin vacuo. The crude residue was purified by silica gel columnchromatography (petroleum ether/EtOAc=4:1) to give the title compound(150 mg, 49%) as yellow oil. LCMS M/Z (M+H) 525.

Step 57-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine

To a solution of tert-butyl7-(7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-2-methyl-2,3-dihydrobenzo[/][1,4]oxazepine-4(5H)-carboxylate(150 mg, 0.29 mmol) in DCM (5 mL) was added trifluoroacetic acid (0.81mL, 10.83 mmol). The mixture was stirred at room temperature for 1 h andconcentrated in vacuo to give the title compound (120 mg, 99%) as ayellow solid that required no further purification. LCMS M/Z (M+H) 425

Step 67-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxamide

To a solution of7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-2-methyl-2,3,4,5-tetrahydrobenzo[][1,4]oxazepine (120 mg, 0.28 mmol) in DCM (5 mL) was addedtriethylamine (0.12 mL, 0.85 mmol) andN-methyl-1H-imidazole-1-carboxamide (42 mg, 0.34 mmol). The reactionmixture was stirred at room temperature for 12 h and concentrated invacuo. DCM (10 mL) was added and washed with water (10 mL×3) and brine(30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The crude residue was purified by reverse phase chromatography(acetonitrile 42-72%/0.05% NH₄OH in water) to give the title compound(83 mg, 61%) as yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.55 (s, 1H),7.42 (s, 1H), 7.12-7.06 (m, 4H), 6.97 (s, 1H), 6.49 (t, J=55.2 Hz, 1H),4.45-4.28 (m, 3H), 4.21-4.17 (m, 1H), 4.05-4.03 (m, 1H), 3.96 (s, 3H),3.62 (t, J=5.6 Hz, 2H), 3.30-3.24 (m, 1H), 2.94-2.85 (m, 2H), 2.78 (d,J=4.4 Hz, 3H), 2.09-2.05 (m, 2H), 1.38 (d, J=6.0 Hz, 3H). LCMS M/Z(M+Na) 504

Example 115(R)-8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one

Step 1 (R)-methyl 2-(2-bromo-6-nitrophenoxy)propanoate

To a solution of 2-bromo-6-nitrophenol (2.0 g, 9.17 mmol), (S)-methyl2-hydroxypropanoate (1.15 g, 11.01 mmol) and triphenylphosphine (3.61 g,13.76 mmol) in DCM (20 mL) was added DIAD (2.78 mL, 13.76 mmol)dropwise. The reaction mixture was stirred at room temperature for 15 hunder a nitrogen atmosphere. The mixture was concentrated in vacuo.EtOAc (80 mL) was added, washed with brine (30 mL×3), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude residuewas purified by silica gel column chromatography (petroleumether/EtOAc=7:3) to give the title compound (2.5 g, 81%) as a whitesolid.

Step 2 (R)-8-bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one

To a solution of (R)-methyl 2-(2-bromo-6-nitrophenoxy)propanoate (3.3 g,10.85 mmol) in AcOH (45 mL) was Fe powder (3.03 g, 54.26 mmol). Thereaction mixture was heated to 80° C. for 2 h. After cooling to roomtemperature, the mixture was filtered and concentrated in vacuo. EtOAc(80 mL) was added, the mixture was washed with water (60 mL), sat. aq.NaHCO₃ solution (40 mL). The organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo to give the title compound(900 mg, 34%) as a white solid. LCMS M/Z (M+H) 242.

Step 3(R)-8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one

To a solution of (R)-8-bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one(300 mg, 1.24 mmol) and7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline(Intermediate C, 326 mg, 1.24 mmol) in 1,4-dioxane (3 mL) was addeddichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)(98 mg, 0.12 mmol) and t-BuONa (357 mg, 3.72 mmol). The reaction mixturewas heated to 120° C. for 16 h under a nitrogen atmosphere. Aftercooling the reaction to room temperature, the mixture was filtered andconcentrated in vacuo. The crude residue was purified by reverse phasechromatography (acetonitrile 20-50%/0.2% formic acid in water) to givethe title compound (2 mg, 0.4%) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 7.72 (s, 1H), 7.54 (s, 1H), 7.41 (s, 1H), 7.05-6.96 (m, 3H),6.72-6.68 (m, 2H), 6.49 (t, J=55.6 Hz, 1H), 4.61 (d, J=6.4 Hz, 1H), 3.96(s, 3H), 3.63-3.58 (m, 2H), 2.94-2.90 (m, 2H), 2.10 (t, J=6.4 Hz, 2H),1.44 (d, J=6.4 Hz, 3H). LCMS M/Z (M+H) 425.

Example 1165-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-3-methyl-3,4-dihydroquinazolin-2(1H)-one

Step 1 1-bromo-2-(bromomethyl)-3-nitrobenzene

To a solution of 1-bromo-2-methyl-3-nitrobenzene (3.0 g, 13.89 mmol) inCCl₄ (20 mL) was added NBS (2.47 g, 13.89 mmol) and BPO (336 mg, 1.39mmol). The reaction mixture was heated to 80° C. for 12 h. After coolingthe reaction to room temperature, the mixture was concentrated in vacuo.EtOAc (20 mL) was added, washed with water (20 mL×2) and brine (20 mL).The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by silica gelcolumn chromatography (petroleum ether/EtOAc=4:1) to give the titlecompound (3.2 g, 78%) as a yellow solid.

Step 2 1-(2-bromo-6-nitrophenyl)-N-methylmethanamine

To a solution of methanamine in THF (2.0 M, 50 mL, 100 mmol) was added1-bromo-2-(bromomethyl)-3-nitrobenzene (3.0 g, 10.17 mmol). The reactionmixture was stirred room temperature for 12 h. DCM (50 mL) was added andthe mixture was washed with water (50 mL×3), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The crude residue waspurified by Prep-TLC (petroleum ether/EtOAc=4:1) to give the titlecompound (1.6 g, 64%) as a yellow solid.

Step 3 3-bromo-2-((methylamino)methyl)aniline

To a solution of 1-(2-bromo-6-nitrophenyl)-N-methylmethanamine (1.5 g,6.12 mmol) in acetic acid (40 mL) was added Fe powder (342 mg, 6.12mmol). The reaction mixture was stirred at room temperature for 2 h.Insoluble solid was filtered off, the filtrate was adjusted to pH 8 byadding sat. aq. NaHCO₃ and extracted with EtOAc (20 mL). The organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated invacuo to give the title compound (800 mg, 61%) as a yellow solid thatrequired no further purification.

Step 4 5-bromo-3-methyl-3,4-dihydroquinazolin-2(1H)-one

To a solution of 3-bromo-2-((methylamino)methyl)aniline (700 mg, 3.25mmol) in DCM (10 mL) was added di(1H-imidazol-1-yl)methanone (792 mg,4.88 mmol). The reaction mixture was stirred at room temperature for 12h. DCM (20 mL) was added and washed with water (20 mL×2), brine (20 mL),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude residue was purified by silica gel column chromatography(petroleum ether/EtOAc=4:1) to give the title compound (400 mg, 51%) asa yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.12 (d, J=8.0 Hz, 1H),7.04-6.99 (m, 1H), 6.65 (d, J=7.2 Hz, 1H), 4.47 (s, 2H), 3.06 (s, 3H).

Step 55-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-3-methyl-3,4-dihydroquinazolin-2(1H)-one

To a solution of 5-bromo-3-methyl-3,4-dihydroquinazolin-2(1H)-one (100mg, 0.32 mmol) in 1,4-dioxane (2 mL) was added7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline(Intermediate C, 84 mg, 0.32 mmol), t-BuONa (92 mg, 0.95 mmol) anddichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)(25 mg, 0.03 mmol). The mixture was irradiated in a microwave at 150° C.for 4 h. The mixture was filtered and concentrated in vacuo. The cruderesidue was purified by reverse phase chromatography (acetonitrile38-68%/0.2% formic acid in water) give the title compound (5 mg, 4%) asa white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.47 (s, 1H), 7.34 (s, 1H),7.16 (s, 1H), 7.00 (s, 1H), 6.77 (d, J=8.0 Hz, 1H), 6.61 (s, 1H),6.54-6.25 (m, 3H), 4.22 (s, 2H), 3.88 (s, 3H), 2.91-2.86 (m, 2H), 2.88(s, 3H), 2.06-2.03 (m, 2H), 1.52-1.49 (m, 2H). LCMS M/Z (M+H) 424.

Example 117 and 118(S)-2-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carboxamide&(R)-2-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carboxamide

Step 1: methyl2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carboxylate

To a solution of 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine (500 mg,3.26 mmol) in diethyl ether (30 mL) at −30° C. was added LiHMDS (2 M inTHF, 3.26 mL, 6.51 mmol) dropwised under a nitrogen atmosphere. Themixture was stirred at −30° C. for 1 h and dimethyl carbonate (0.30 mL,3.58 mmol) was added. After stirring at −30° C. for 1 h, the mixture waswarmed to room temperature and stirred for an additional 12 h. Thereaction mixture was quenched with sat. aq. NH₄Cl (20 mL) and extractedwith DCM (20 mL). The organic layer was washed with water (20 mL×2),brine (20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The crude residue was purified by silica gel columnchromatography (EtOAc) to give the title compound (260 mg, 38%) ascolorless oil. LCMS M/Z (M+H) 212.

Step 22-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-(2H)-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carboxylicacid

To a solution of7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline(Intermediate C, 187 mg, 0.71 mmol) in 1,4-dioxane (3 mL) was addedmethyl 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carboxylate (150mg, 0.71 mmol), t-BuONa (170 mg, 1.77 mmol),2-dicyclohexylphosphino-2′,6′-di-1-propoxy-1,1′-biphenyl (33 mg, 0.07mmol) andchloro(2-dicyclohexylphosphino-2′,6′-di-1-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)(55 mg, 0.07 mmol). The reaction mixture was heated to 110° C. for 16 hunder a nitrogen atmosphere. After cooling the reaction to roomtemperature, the mixture was filtered and concentrated in vacuo. Thecrude residue was purified by silica gel column chromatography(DCM/MeOH=10:1) to give the title compound (260 mg, 48%) as dark oil.LCMS M/Z (M+H) 425.

Step 3(S)-2-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carboxamide&(R)-2-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carboxamide

To a solution of2-(7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carboxylicacid (260 mg, 0.61 mmol) in DMF (5 mL), HATU (303 mg, 0.80 mmol) andN,N-diisopropylethylamine (0.41 mL, 2.45 mmol) was added methanaminehydrochloride (50 mg, 0.74 mmol). The reaction mixture was stirred atroom temperature for 1 h and concentrated in vacuo. The crude residuewas purified by reverse phase chromatography (acetonitrile 40-70%/0.05%NH₄OH in water) to give the racemic compound (40 mg, 15%) as a whitesolid that was separated by using chiral SFC (Chiralpak AD 250×30 mmI.D., 5 um; Supercritical CO₂/EtOH+NH₃.H₂O=70/30; 60 mL/min) to give(S)-2-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carboxamide(Example 117, 15 mg, first peak) as a white solid and(R)-2-(7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carboxamide(Example 118, 8 mg, second peak) as a white solid. Absoluteconfiguration was arbitrarily assigned to each enantiomer. Example 117:¹H NMR (400 MHz, DMSO-d₆) δ 7.97-7.93 (m, 1H), 7.80 (s, 1H), 7.56-7.50(m, 2H), 7.43 (s, 1H), 7.20 (s, 1H), 6.97-6.93 (m, 1H), 6.82 (d, J=55.2Hz, 1H), 3.86 (s, 3H), 3.81-3.69 (m, 3H), 2.94-2.75 (m, 4H), 2.59 (d,J=4.8 Hz, 3H), 2.26-2.17 (m, 2H), 1.94-1.86 (m, 2H). LCMS M/Z (M+H) 438.Example 118: ¹H NMR (400 MHz, DMSO-d₆) δ 7.99-7.96 (m, 1H), 7.82 (s,1H), 7.56-7.50 (m, 2H), 7.46 (s, 1H), 7.22 (s, 1H), 6.99-6.96 (m, 1H),6.84 (d, J=55.2 Hz, 1H), 3.88 (s, 3H), 3.79-3.42 (m, 3H), 2.94-2.75 (m,4H), 2.58-2.59 (m, 3H), 2.30-2.17 (m, 2H), 1.98-1.84 (m, 2H). LCMS M/Z(M+H) 438.

Example 1194-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methylisoquinoline-6-carboxamide

Step 1 methyl 4-bromoisoquinoline-6-carboxylate

To a solution of methyl isoquinoline-6-carboxylate (700 mg, 3.74 mmol)in acetic acid (9 mL) was added NBS (798.67 mg, 4.49 mmol). The reactionmixture was heated to 90° C. for 2 h.

After cooling the reaction to room temperature, the mixture wasconcentrated in vacuo. The crude residue was purified by silica gelcolumn chromatography (petroleum ether/EtOAc=3:1) to give the titlecompound (600 mg, 60%) as a brown solid. LCMS M/Z (M+H) 266.

Step 24-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoquinoline-6-carboxylicacid

To a solution of methyl 4-bromoisoquinoline-6-carboxylate (300 mg, 1.13mmol),7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline(Intermediate C, 297 mg, 1.13 mmol) and K₃PO₄ (718 mg, 3.38 mmol) in2-methyl-2-butanol (10 mL) was addedmethanesulfonato(2-dicyclohexylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)(95 mg, 0.11 mmol). The reaction mixture was heated to 100° C. for 16 hunder a nitrogen atmosphere. After cooling the reaction to roomtemperature, the mixture was filtered and concentrated in vacuo. Thecrude residue was purified by silica gel column chromatography(DCM/MeOH=10:1) to give the title compound (270 mg, 55%) as a brownsolid. LCMS M/Z (M+H) 435.

Step 34-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-(2H)-yl)-N-methylisoquinoline-6-carboxamide

To a solution of4-(7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoquinoline-6-carboxylicacid (100 mg, 0.23 mmol), N,N-diisopropylethylamine (0.082 mL, 0.46mmol) and HATU (105 mg, 0.28 mmol) in DMF (3 mL) was added methanaminehydrochloride (19 mg, 0.28 mmol). The reaction mixture was stirred atroom temperature for 3 h and concentrated in vacuo. The crude residuewas purified by reverse phase chromatography (acetonitrile 40-70%/0.2%formic acid in water) to afford the title compound (28 mg, 25%) as awhite solid. ¹H NMR (400 MHz, CDC₃) δ 9.41 (s, 1H), 8.83 (d, J=4.4 Hz,1H), 8.58 (s, 1H), 8.38-8.33 (m, 2H), 8.14 (d, J=9.2 Hz, 1H), 7.74 (s,1H), 7.49 (s, 1H), 7.19 (s, 1H), 6.65 (t, J=55.2 Hz, 1H), 6.12 (s, 1H),3.85 (s, 3H), 3.70 (t, J=5.6 Hz, 2H), 3.02-2.99 (m, 2H), 2.81 (d, J=4.4Hz, 3H), 2.17-2.16 (m, 2H). LCMS M/Z (M+H) 448.

Example 1207-(difluoromethyl)-N-methyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-[1,8′-biquinoline]-2′-carboxamide

Step 1 8-bromo-N-methylquinoline-2-carboxamide

To a solution of 8-bromoquinoline-2-carboxylic acid (300 mg, 1.2 mmol),HATU (543 mg, 1.4 mmol) and N,N-diisopropylethylamine (0.62 mL, 3.57mmol) in DMF (5 mL) was added methanamine hydrochloride (161 mg, 2.4mmol). The reaction mixture was stirred at room temperature for 16 h andconcentrated in vacuo. The crude residue was purified by silica gelcolumn chromatography (petroleum ether/EtOAc=1:1) to give the titlecompound (180 mg, 57%) as a yellow solid. LCMS M/Z (M+H) 265.

Step 27-(difluoromethyl)-N-methyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-2H-[1,8′-biquinoline]-2′-carboxamide

To a solution of 8-bromo-N-methyl-quinoline-2-carboxamide (100 mg, 0.22mmol),7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline(Intermediate C, 115 mg, 0.44 mmol) and t-BuONa (63 mg, 0.66 mmol) in1,4-dioxane (5 mL) was addeddichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)(17 mg, 0.02 mmol). The reaction mixture was heated to 120° C. for 16 hunder a nitrogen atmosphere. After cooling to room temperature, thereaction was concentrated in vacuo. DCM (50 mL) was added and washedwith water (30 mL×3), brine (20 mL). The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude residuewas purified by reverse phase chromatography (acetonitrile 46-76%/0.05%NH₄OH in water) to give the title compound (16 mg, 16%) as a yellowsolid. H NMR (400 MHz, DMSO-d₆) δ 8.62 (d, J=8.4 Hz, 1H), 8.13 (d, J=8.4Hz, 1H), 7.97-7.95 (m, 1H), 7.84-7.80 (m, 1H), 7.79-7.72 (m, 3H), 7.51(s, 1H), 7.22 (s, 1H), 6.67 (t, J=56.0 Hz, 1H), 6.45 (s, 1H), 3.86 (s,3H), 2.99-2.96 (m, 2H), 2.76 (d, J=5.2 Hz, 3H), 2.57-2.53 (m, 2H),2.11-2.06 (m, 2H). LCMS M/Z (M+H) 448.

Example 121N-methyl-2-(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)benzo[d]oxazole-4-carboxamide

Step 1 methyl2-(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)benzo[d]oxazole-4-carboxylate

To a solution of 8-chloro-3-(1-methyl-1H-pyrazol-4-yl)isoquinoline(Intermediate D, 310 mg, 1.27 mmol), methylbenzo[d]oxazole-4-carboxylate (150 mg, 0.85 mmol) and K₃PO₄ (539 mg,2.54 mmol) in NMP (8 mL) were added bis(1-adamantyl)-butyl-phosphane (61mg, 0.17 mmol) palladium(II) acetate (19 mg, 0.08 mmol). The reactionmixture was stirred at room temperature for 15 min and heated to 125° C.for 24 h under a nitrogen atmosphere. After cooling the reaction to roomtemperature, the mixture was filtered and concentrated in vacuo.

The crude residue was purified by silica gel column chromatography(petroleum ether/EtOAc=3:1) to give the title compound (150 mg, 46%) asa brown solid. LCMS M/Z (M+H) 385.

Step 22-(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)benzo[d]oxazole-4-carboxylicacid

To a solution of methyl2-(3-(1-methyl-H-pyrazol-4-yl)isoquinolin-8-yl)benzo[d]oxazole-4-carboxylate(150 mg, 0.39 mmol) in MeOH (10 mL) and water (2 mL) was added lithiumhydroxide monohydrate (82 mg, 1.95 mmol). The reaction mixture wasstirred at room temperature for 2 h. The mixture was quenched with water(15 mL) and extracted with EtOAc (15 mL×3). The combined organic layerswere dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo togive the title compound (90 mg, 62%) as a brown solid. LCMS M/Z (M+H)371.

Step 3N-methyl-2-(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)benzo[d]oxazole-4-carboxamide

To a solution of2-(3-(1-methyl-H-pyrazol-4-yl)isoquinolin-8-yl)benzo[d]oxazole-4-carboxylicacid (80 mg, 0.22 mmol), N,N-diisopropylethylamine (0.077 mL, 0.43 mmol)and HATU (99 mg, 0.26 mmol) in DMF (4 mL) was added methanaminehydrochloride (22 mg, 0.32 mmol). The reaction mixture was stirred atroom temperature for 2 h and concentrated in vacuo. The crude residuewas purified by reverse phase chromatography (acetonitrile 20-50%/0.2%formic acid in water) to give the title compound (2 mg, 2%) as a whitesolid. H NMR (400 MHz, CDCl₃) δ 10.58 (s, 1H), 8.97 (s, 1H), 8.48 (d,J=6.8 Hz, 1H), 8.33 (d, J=7.6 Hz, 1H), 8.12 (s, 1H), 8.05 (d, J=8.0 Hz,1H), 7.91 (s, 1H), 7.85-7.81 (m, 2H), 7.59-7.57 (m, 1H), 4.03 (s, 3H),3.23 (d, J=4.8 Hz, 3H). LCMS M/Z (M+H) 384.

Example 1221-(6-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)pyridin-2-yl)-3-methylurea

Step 1 tert-butyl (6-bromopyridin-2-yl)carbamate

To a solution of 6-bromopyridin-2-amine (1.0 g, 5.78 mmol),di-tert-butyl dicarbonate (1.4 g, 6.2 mmol) in DCM (10 mL) were addedtriethylamine (1.58 mL, 11.91 mmol) and 4-dimethylaminopyridine (140 mg,1.17 mmol). The reaction mixture was stirred at room temperature for 10h and concentrated in vacuo. The crude residue was purified by silicagel column chromatography (petroleum ether/EtOAc=10:1) to give the titlecompound (1.1 g, 67%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ7.55-7.48 (m, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.19 (t, J=4.0 Hz, 2H), 1.44(s, 9H).

Step 2tert-butyl(6-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)pyridin-2-yl)carbamate

To a solution of7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline(Intermediate C, 290 mg, 1.1 mmol), tert-butyl(6-bromopyridin-2-yl)carbamate (301 mg, 1.1 mmol) and t-BuONa (265 mg,2.75 mmol) in 1,4-dioxane (2 mL) was addeddichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)(86 mg, 0.11 mmol). The reaction mixture was heated to 120° C. for 12 hunder a nitrogen atmosphere. After cooling the reaction to roomtemperature, the mixture was filtered and concentrated in vacuo. Thecrude residue was purified by silica gel column chromatography(petroleum ether/EtOAc=1:1) to give the title compound (402 mg, 80%) asyellow oil. LCMS M/Z (M+H) 456.

Step 36-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)pyridin-2-amine

To a solution of tert-butyl(6-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)pyridin-2-yl)carbamate(402 mg, 0.88 mmol) in DCM (4 mL) was added trifluoroacetic acid (0.65mL, 8.84 mmol) dropwised. The reaction mixture was stirred at roomtemperature for 1 h and concentrated in vacuo to give the title compound(285 mg, 91%) as yellow oil that required no further purification. LCMSM/Z (M+H) 356.

Step 41-(6-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)pyridin-2-yl)-3-methylurea

To a solution of6-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)pyridin-2-amine(258 mg, 0.73 mmol) in DMF (3 mL) at 0° C. was added NaH (60%, 43 mg,1.09 mmol). The mixture was stirred at 0° C. for 10 min,N-methyl-1H-imidazole-1-carboxamide (109 mg, 0.87 mmol) was added. Thereaction mixture was stirred at room temperature for an additional 5 h.The reaction was poured into water (50 mL) and extracted with EtOAc (30mL×3). The combined organic layers were washed with brine (30 mL×2),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude residue was purified by reverse phase chromatography (acetonitrile38-68%/0.05% NH₄OH in water) to give the title compound (57 mg, 19%) asa white solid. H NMR (400 MHz, DMSO-d) S 9.16 (s, 1H), 8.01 (s, 1H),7.85 (s, 1H), 7.62-7.51 (m, 2H), 7.47 (s, 1H), 7.28 (s, 1H), 6.90 (t,J=55.2 Hz, 1H), 6.70 (d, J=8.0 Hz, 1H), 6.62 (d, J=8.0 Hz, 1H), 3.89 (s,3H), 3.74 (t, J=6.4 Hz, 2H), 2.78 (t, J=5.6 Hz, 2H), 2.48 (s, 3H),1.96-1.90 (m, 2H). LCMS M/Z (M+H) 413.

Example 1231-(6-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)₄-methoxypyridin-2-yl)-3-methylurea

Step 1 tert-butyl (6-bromo-4-methoxypyridin-2-yl)carbamate

To a solution of 2,6-dibromo-4-methoxypyridine (2 g, 7.49 mmol),tert-butyl carbamate (877 mg, 7.49 mmol) and Cs₂CO₃(4.8 g, 14.98 mmol)in 1,4-dioxane (50 mL) were added palladium(II) acetate (168 mg, 0.75mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (433 mg, 0.75mmol). The reaction mixture was heated to 100° C. for 16 h under anitrogen atmosphere. After cooling the reaction to room temperature,water (100 mL) was added and extracted with EtOAc (50 mL×3). Thecombined organic layers were washed with brine (50 mL×2), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude residuewas purified by silica gel column chromatography (petroleumether/EtOAc=9:1) to give the title compound (900 mg, 39%) as a whitesolid. LCMS M/Z (M+H) 303.

Step 2 tert-butyl(6-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4-methoxypyridin-2-yl)arbamate

To a solution of tert-butyl (6-bromo-4-methoxypyridin-2-yl)carbamate(460 mg, 1.52 mmol),7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline(Intermediate C, 400 mg, 1.52 mmol) and t-BuONa (436 mg, 4.54 mmol) in1,4-dioxane (15 mL) was addeddichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)(120 mg, 0.15 mmol). The reaction mixture was heated to 120° C. for 16 hunder a nitrogen atmosphere. After cooling the reaction to roomtemperature, water (50 mL) was added and extratcted with EtOAc (30mL×3). The combined organic layers were washed with brine (30 mL×2),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude residue was purified by Prep-TLC (petroleum ether/EtOAc=2:1) togive the title compound (100 mg, 14%) as a white solid.

Step 36-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4-methoxypyridin-2-amine

To a solution of tert-butyl(6-(7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4-methoxypyridin-2-yl)carbamate(100 mg, 0.21 mmol) in DCM (10 mL) at 0° C. was added trifluoroaceticacid (0.076 mL, 1.03 mmol). The reaction mixture was stirred at roomtemperature for 5 h and concentrated in vacuo to give the title compound(80 mg, crude) as yellow oil that required no further purification. LCMSM/Z (M+H) 386.

Step 41-(6-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)₄-methoxypyridin-2-yl)-3-methylurea

To a solution of6-(7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4-methoxypyridin-2-amine(40 mg, 0.1 mmol) in anhydrous DMF (2 mL) at 0° C. was added NaH (60%,20 mg, 0.5 mmol). After stirring at 0° C. for 10 min,N-methyl-1H-imidazole-1-carboxamide (36 mg, 0.29 mmol) was added. Thereaction solution was stirred at room temperature for an additional 2 h.The reaction mixture was poured into water (50 mL) and extracted withEtOAc (30 mL×3). The combined organic layers were washed with brine (30mL×2), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo.The crude residue was purified by reverse phase chromatography(acetonitrile 40-70%/0.2% formic acid in water) to give the titlecompound (8 mg, 18%) as a white solid. H NMR (400 MHz, CDCl₃) δ 8.88 (s,1H), 7.69 (s, 1H), 7.60 (s, 1H), 7.49 (s, 1H), 7.18 (s, 1H), 7.06 (s,1H), 6.58 (t, J=55.2 Hz, 1H), 6.17 (s, 1H), 5.75 (s, 1H), 3.99 (s, 3H),3.81-3.76 (m, 2H), 3.79 (s, 3H), 2.82-2.80 (m, 2H), 2.70 (d, J=4.0 Hz,3H), 2.06 (t, J=6.0 Hz, 2H). LCMS M/Z (M+H) 443.

Example 124N⁴,1-dimethyl-N³-(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-1H-pyrazole-3,4-dicarboxamide

Step 1N-(diphenylmethylene)-3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-amine

To a solution of 8-chloro-3-(1-methyl-1H-pyrazol-4-yl)isoquinoline(Intermediate D, 400 mg, 1.64 mmol), diphenylmethanimine (446 mg, 2.46mmol) and t-BuONa (473 mg, 4.92 mmol) in 1,4-dioxane (8 mL) was addeddichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)(130 mg, 0.16 mmol). The reaction mixture was heated to 120° C. for 16 hunder a nitrogen atmosphere. After cooling to room temperature, thereaction was filtered and concentrated in vacuo. The residue waspurified by silica gel column chromatography (petroleum ether/EtOAc=1:1)to give the title compound (500 mg, 78%) as a yellow solid. ¹H NMR (400MHz, CDCl₃) δ 9.40 (s, 1H), 8.02 (d, J=6.4 Hz, 2H), 7.89 (d, J=7.6 Hz,2H), 7.69 (s, 1H), 7.58-7.40 (m, 3H), 7.35-7.34 (m, 2H), 7.24-7.02 (m,5H), 6.54-6.50 (m, 1H), 3.98 (s, 3H).

Step 2 3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-amine

To a solution ofN-(diphenylmethylene)-3-(1-methyl-H-pyrazol-4-yl)isoquinolin-8-amine(500 mg, 1.29 mmol) in THF (6 mL) was added HCl (2N, 6.44 mL, 12.87mmol) dropwise. The resulting mixture was stirred at room temperaturefor 2 h and concentrated in vacuo. The crude residue was washed withTBME (10 mL) to give the title compound (280 mg, 97%) as an orangesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.72 (s, 1H), 8.69 (s, 1H), 8.36-8.34(m, 2H), 7.80-7.75 (m, 1H), 7.12 (d, J=7.6 Hz, 1H), 6.88 (d, J=8.0 Hz,1H), 3.97 (s, 3H).

Step 34-bromo-1-methyl-N-(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-1H-pyrazole-3-carboxamide

To a solution of 4-bromo-1-methyl-1H-pyrazole-3-carboxylic acid (450 mg,2.2 mmol) in DCM (10 mL) was added oxalyl dichloride (0.37 mL, 4.39mmol) and DMF (0.016 mL, 0.22 mmol). The mixture was stirred at roomtemperature for 2 h and concentrated in vacuo to give4-bromo-1-methyl-1H-pyrazole-3-carbonyl chloride (500 mg, crude) as awhite solid which was dissolved in DCM (15 mL).3-(1-Methyl-H-pyrazol-4-yl)isoquinolin-8-amine (350 mg, 1.56 mmol) andN,N-diisopropylethylamine (1.09 mL, 6.24 mmol) were added. The reactionmixture was stirred at room temperature for 16 h. The reaction waswashed with water (5 mL). The organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The crude residue waspurified by silica gel column chromatography (DCM/MeOH=20:1) to give thetitle compound (400 mg, 62%) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 10.55 (s, 1H), 9.28 (s, 1H), 8.33 (s, 1H), 8.17 (s, 1H),8.08-8.06 (m, 2H), 7.77-7.71 (m, 2H), 7.69-7.64 (m, 1H), 4.01 (s, 3H),3.92 (s, 3H).

Step 4 methyl1-methyl-3-((3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)carbamoyl)-1H-pyrazole-4-carboxylate

To a solution of4-bromo-1-methyl-N-(3-(1-methyl-H-pyrazol-4-yl)isoquinolin-8-yl)-1H-pyrazole-3-carboxamide(300 mg, 0.73 mmol) in MeOH (10 mL) was added triethylamine (0.51 mL,3.65 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (53 mg, 0.07mmol). The reaction mixture was heated to 70° C. for 72 h under a carbonmonoxide atmosphere (50 psi). After cooling the reaction to roomtemperature, the reaction was filtered and concentrated in vacuo. Thecrude residue was purified by silica gel column chromatography(DCM/MeOH=10:1) to give the title compound (200 mg, 70%) as a yellowsolid. LCMS M/Z (M+H) 391.

Step 51-methyl-3-((3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)carbamoyl)-1H-pyrazole-4-carboxylicacid

To a solution of methyl1-methyl-3-((3-(1-methyl-H-pyrazol-4-yl)isoquinolin-8-yl)carbamoyl)-1H-pyrazole-4-carboxylate(100 mg, 0.26 mmol) in MeOH (1 mL), THF (3 mL) and Water (0.5 mL) wasadded lithium hydroxide monohydrate (54 mg, 1.28 mmol). The reactionmixture was stirred at room temperature for 16 h and concentrated invacuo. Water (1 mL) was added and the mixture was acidified with HCl (1N) to pH 6 and then extracted with DCM/MeOH (10/1, 10 mL×3). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (50 mg, 52%) as ayellow solid that required no further purification. LCMS M/Z (M+H) 377.

Step 6N⁴,1-dimethyl-N³-(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-1H-pyrazole-3,4-dicarboxamide

To a solution of1-methyl-3-((3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)carbamoyl)-1H-pyrazole-4-carboxylicacid (50 mg, 0.13 mmol), HATU (76 mg, 0.20 mmol) andN,N-diisopropylethylamine (0.09 mL, 0.53 mmol) in DMF (2 mL) was addedmethanamine hydrochloride (18 mg, 0.27 mmol). The reaction mixture wasstirred at room temperature for 16 h. The crude residue was purified byreverse phase chromatography (acetonitrile 24-54%/0.05% NH4OH in water)to give the title compound (19 mg, 37%) as a pale yellow solid. ¹H NMR(400 MHz, DMSO-d₆) δ 9.57-9.53 (m, 1H), 9.39 (s, 1H), 8.42 (s, 1H), 8.34(s, 1H), 8.09-8.07 (m, 2H), 7.84-7.69 (m, 3H), 4.03 (s, 3H), 3.91 (s,3H), 2.78 (d, J=4.4 Hz, 3H). LCMS M/Z (M+H) 390.

Example 1253-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-b]pyridine-5-carboxamide

Step 1 methyl 3-bromo-1H-pyrazolo[4,3-b]pyridine-5-carboxylate

To a solution of methyl 1H-pyrazolo[4,3-b]pyridine-5-carboxylate (800mg, 4.52 mmol) in THF (10 mL) was added NBS (1.21 g, 6.77 mmol). Thereaction mixture was stirred at room temperature for 12 h andconcentrated in vacuo. DCM (30 mL) was added and washed with water (30mL×2), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuoto give the title compound (483 mg, 42%) as a yellow solid that requiredno further purification. LCMS M/Z (M+H) 256.

Step 2 methyl3-bromo-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-b]pyridine-5-carboxylate

To a stirred solution of methyl3-bromo-1H-pyrazolo[4,3-b]pyridine-5-carboxylate (480 mg, 1.87 mmol) inDMF (20 mL) was added tetrahydro-2H-pyran-4-yl methanesulfonate (507 mg,2.81 mmol) and Cs₂CO₃ (1.83 g, 5.62 mmol). The reaction mixture washeated to 80° C. for 16 h under a nitrogen atmosphere. After cooling thereaction to room temperature, the mixture was filtered and concentratedin vacuo. The residue was dissolved in DCM (30 mL) and washed with water(30 mL×2). The organic layer was dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo. The crude residue was purified by silica gelcolumn chromatography (DCM/MeOH=100:1) to give the title compound (360mg, 57%) as yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.51 (d, J=8.8 Hz,1H), 8.17 (d, J=8.8 Hz, 1H), 5.13-4.19 (m, 1H), 4.03-4.00 (m, 2H), 3.94(s, 3H), 3.54 (t, J=11.6 Hz, 2H), 2.12-2.06 (m, 2H), 1.96-1.93 (m, 2H).

Step 33-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-b]pyridine-5-carboxylicacid

To a solution of7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline(Intermediate C, 77 mg, 0.29 mmol), methyl3-bromo-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-b]pyridine-5-carboxylate(100 mg, 0.29 mmol) and K₃PO₄ (187 mg, 0.88 mmol) in 2-methyl-2-butanol(5 mL) was addedmethanesulfonato(2-dicyclohexylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)(25 mg, 0.03 mmol). The mixture was heated to 95° C. for 12 h under anargon atmosphere. After cooling the reaction to room temperature, themixture was filtered and concentrated in vacuo. The crude residue waspurified by silica gel column chromatography (DCM/MeOH=10:1) to give thetitle compound (100 mg, 67%) as yellow oil. LCMS M/Z (M+H) 509.

Step 43-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-(2H)-yl)-N-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-b]pyridine-5-carboxamide

To a solution of3-(7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-b]pyridine-5-carboxylicacid (100 mg, 0.20 mmol), N,N-diisopropylethylamine (0.104 mL, 0.59mmol) and HATU (150 mg, 0.39 mmol) in DMF (2.5 mL) was added methanaminehydrochloride (27 mg, 0.39 mmol). The reaction mixture was stirred atroom temperature for 1 h and concentrated in vacuo. The crude residuewas purified by reverse phase chromatography (acetonitrile 41-71%/0.05%NH₄OH in water) to give the title compound (0.6 mg, 0.6%) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.40-8.29 (m, 2H), 8.08 (d, J=8.8 Hz,1H), 7.80 (s, 1H), 7.67 (s, 1H), 7.57-7.51 (m, 1H), 7.20 (s, 1H), 6.82(t, J=55.6 Hz, 1H), 5.00-4.88 (m, 1H), 4.24-4.18 (m, 2H), 4.02-3.98 (m,2H), 3.88 (s, 3H), 3.55 (t, J=11.2 Hz, 2H), 2.96-2.89 (m, 2H), 2.85 (d,J=4.8 Hz, 3H), 2.14-2.03 (m, 4H), 1.94-1.91 (m, 2H). LCMS M/Z (M+H) 522.

Example 1263-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide

Step 1 ethyl1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate

To a solution of ethyl3-bromo-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate (5.0 g, 25.74 mmol)and Cs₂CO₃ (16.77 g, 51.49 mmol) in DMF (10 mL) was addedtetrahydro-2H-pyran-4-yl methanesulfonate (9.28 g, 51.49 mmol). Thereaction was heated to 80° C. for 12 h. After cooling to roomtemperature, the reaction was concentrated in vacuo. EtOAc (80 mL) wasadded and washed with water (100 mL×3), brine (100 mL). The organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The crude residue was purified by silica gel chromatography(petroleum ether/5% MTBE in THF=1:1) to give the title compound (5.3 g,74%) as colorless oil (a mixture of positional isomers about 7:5). LCMSM/Z (M+H) 279.

Step 2 ethyl3-bromo-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate

To a solution of ethyl1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate(1.5 g, 5.39 mmol) was added NBS (96 mg, 5.39 mmol) in acetonitrile (10mL). The reaction mixture was stirred at room temperature for 2 h. Themixture was quenched with water (50 mL) and extracted with EtOAc (30mL×3). The combined organic layers were dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The crude residue was purified bysilica gel chromatography (petroleum ether/MTBE/THF/=20:1:1) to give thetitle compound (1.0 g, 52%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ4.18 (q, J=7.2 Hz, 2H), 4.12-4.08 (m, 2H), 3.51-3.45 (m, 2H), 2.82-2.55(m, 5H), 2.33-2.23 (m, 3H), 1.96-1.76 (m, 3H), 1.29 (t, J=7.2 Hz, 3H).LCMS M/Z (M+H) 357.

Step 3 ethyl3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate

To a solution of7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline(Intermediate C, 177 mg, 0.67 mmol) and ethyl3-bromo-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate(200 mg, 0.56 mmol) in 2-methyl-2-butanol (2 mL) was addedmethanesulfonato(2-dicyclohexylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)(474 mg, 0.56 mmol) and K₃PO₄ (119 mg, 0.56 mmol). The reaction mixturewas heated to 110° C. for 16 h under a nitrogen atmosphere. Aftercooling to room temperature, the reaction was concentrated in vacuo. DCM(50 mL) was added and washed with water (30 mL×3), brine (20 mL). Theorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo. The crude residue was purified by silica gel chromatography(eluent from petroleum ether/EtOAc=2:1 to 1:2) to give the titlecompound (130 mg, 43%) as yellow oil. LCMS M/Z (M+H) 540.

Step 43-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylicacid

To a solution of ethyl3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate(130 mg, 0.24 mmol) in THF (5 mL) was added lithium hydroxidemonohydrate (50 mg, 1.2 mmol). The mixture was stirred at roomtemperature for 3 h and concentrated in vacuo. Water (10 mL) was addedand the mixture was acidified with citric acid (25%) to pH 3 and thenextracted with DCM (50 mL). The organic layer was washed with water (20mL×2), brine (20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (90 mg, 73%) as ayellow solid that required no further purification. LCMS M/Z (M+H) 512.

Step 53-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-(2H)-yl)-N-methyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide

To a solution of3-(7-(difluoromethyl)-6-(1-methyl-H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylicacid (90 mg, 0.18 mmol) and HATU (100 mg, 0.26 mmol) in DMF (2.5 mL) wasadded N,N-diisopropylethylamine (0.1 mL, 0.53 mmol) was addedmethanamine (0.4 mL, 0.4 mmol, 1 M in THF). The reaction mixture wasstirred at room temperature for 1 h. EtOAc (30 mL) was added and washedwith water (30 mL×3), brine (30 mL). The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude residuewas purified by reverse phase chromatography (acetonitrile 30-60%/0.05%NH₄OH in water) to give the title compound (53 mg, 57%) as a yellowsolid. H NMR (400 MHz, DMSO-d₆) δ 7.77-7.71 (m, 2H), 7.48 (s, 1H), 7.06(s, 1H), 6.77 (s, 1H), 6.76 (t, J=55.2 Hz, 1H), 4.30-4.21 (m, 1H),3.97-3.92 (m, 2H), 3.86 (s, 3H), 3.66-3.58 (m, 1H), 3.53-3.42 (m, 3H),2.90-2.80 (m, 3H), 2.66-2.58 (m, 1H), 2.55 (d, J=4.4 Hz, 3H), 2.40-2.30(m, 1H), 2.27-2.23 (m, 2H), 2.04-1.90 (m, 5H), 1.85-1.67 (m, 3H). LCMSM/Z (M+H) 525.

Example 127

IC₅₀ Measurements for Inhibitors Using CBP TR-FRET Binding Assay

His/Flag epitope tagged CBP was cloned, expressed, and purified tohomogeneity. CBP binding and inhibition was assessed by monitoring theengagement of a biotinylated small molecule compound with the targetusing the TR-FRET assay technology (Perkin-Elmer). Specifically, in a384 well ProxiPlate CBP (4 nM final) was combined with biotin-ligand (60nM final) in 50 mM HEPES (pH 7.5), 50 mM NaCl, 1 mM TCEP, 0.01% (w/v)BSA, and 0.008% (w/v) Brij-35 either in the presence of DMSO (final 0.2%DMSO) or compound dilution series in DMSO. After 10 minutes incubationat room temperature, a mixture Eu-W1024 Anti-6×His antibody (“6×His” isdisclosed as SEQ ID NO: 3) (Perkin Elmer ADO110) and SureLight™Allophycocyanin-Streptavidin (APC-SA, Perkin Elmer CR130-100) were addedto a final concentrations of 0.2 nMolar antibody and 50 nMolar APC-SA,respectively. After twenty minutes of equilibration, the plates wereread on an Envision instrument and IC₅₀ calculated using a fourparameter non-linear curve fit.

MYC RPL19 QuantiGene Assay in MV-4-11 Cells

QuantiGene 2.0 Reagent system, Affymetrix: HUMAN MYCN; V-mycmyelocytomatosis viral related oncogene, neuroblastoma derived (avian);NM_005378 SA-15008. 10,000 MV-4-11 cells (GNE in-house) were plated in75 ul complete media: RPMI-1640 (GNE in-house), 10% FBS (LifeTechnologies, cat. no. 10082), 1% Pen-strep (GNE in-house), in 96 wellclear flat bottom plates (Costar, cat. no. 3595). 25 ul compound wasadded for 4 hours at 37 deg C. in a 1:3 serial dilution 10-point doseresponse, with a final DMSO concentration=0.2%. The cells were thenlysed according to the assay kit's protocol and frozen at −80 deg C. Thefollowing day, an appropriate volume of Working Probe Set was preparedby combining the following reagents in the order listed: Nuclease-freewater, Lysis Mixture, Blocking Reagent, and 2.0 Probe Set (MYC orRPL19). 20 ul of the working probe set was added into each assay well onthe capture plate, and then 80 ul of the lysates were transferred intothe assay plates. The capture plate was placed in a 55 deg C. incubatorfor overnight hybridization (16-20 hours). The following day, washbuffer was prepared according to manufacturer's recommendations. Thecapture plates were washed with 300 ul per well of 1× wash buffer threetimes. Then 100 ul Pre-Amplifier was added to the plate for a 60 minuteincubation at 55 deg C. After the incubation, the capture plate waswashed with 300 ul per well of 1× wash buffer three times, and 100 ulAmplifier was added to the plate for a 60 minute incubation at 55 deg C.The capture plate was again washed with 300 ul per well of 1× washbuffer three times, and 100 ul Label Probe was added to the plate for a60 minute incubation at 50 deg C. Then the capture plate was washed with300 ul per well of 1× wash buffer three times, and 100 ul 2.0 Substratewas added to each well of the plate. The plates were incubated at RT for5 minutes in the dark and read on the Envision using the luminescenceprotocol, with an integration time set at 0.2 seconds.

Data for representative compounds from the assays described above isprovided in the following table.

CBP Myc HTRF IC₅₀ Example Compound IC₅₀ (μM) (μM) 1

0.187 2

0.321 3

0.057 4

0.193 5

0.296 6

0.362 7

0.273 8

0.394 9

0.078 10

0.096 11

0.281 12

0.059 13

0.267 14

0.102 15

0.391 16

0.008 0.173 17

0.047 2.66 18

0.019 1.02 19

0.033 20

1.75 21

0.064 22

1.69 23

0.317 24

0.106 25

0.038 26

2.28 27

0.034 28

0.199 29

0.160 30

0.543 31

0.172 32

0.048 33

0.042 1.17 34

>4.9 >10.0 35

0.023 0.428 36

0.014 1.38 37

0.011 0.281 38

0.016 39

0.012 0.208 40

0.072 1.94 41

0.005 0.136 42

0.019 43

0.006 0.115 44

0.026 45

0.004 0.011 46

0.013 0.413 47

0.039 1.11 49

0.022 50

0.009 0.496 51

0.027 52

0.009 2.18 53

0.048 54

0.059 2.29 55

0.004 0.115 56

0.010 4.04 57

0.009 0.302 58

0.009 0.181 59

0.006 0.205 60

0.009 0.108 61

0.026 62

0.012 0.084 63

0.002 0.053 64

0.002 0.143 65

0.005 0.150 66

0.004 0.046 67

0.005 0.358 68

0.015 4.38 69

0.004 0.047 70

0.018 71

0.187 72

0.110 73

0.080 74

0.108 75

0.244 76

0.243 77

0.187 78

0.022 0.780 79

0.077 80

0.206 81

0.102 0.131 82

0.325 83

0.009 0.177 84

0.087 85

0.450 86

0.081 87

0.429 88

0.258 89

0.078 90

0.032 0.096 91

0.481 92

0.042 93

0.095 94

0.090 95

0.030 96

0.009 0.22 97

0.004 0.058 98

0.004 0.086 99

0.019 100

0.010 0.164 101

0.012 102

0.021 103

0.222 104

0.016 0.377 105

0.011 0.086 106

0.016 107

0.016 0.147 108

0.031 0.235 109

0.273 110

0.201 111

0.409 112

0.032 2.10 113

0.014 0.157 114

0.051 115

0.077 116

0.026 117

0.040 118

3.24 119

0.034 120

0.006 0.632 121

0.274 122

0.088 123

0.115 3.38 124

0.014 125

0.002 126

0.184

While a number of embodiments have been described, these examples may bealtered to provide other embodiments that utilize the compounds andmethods described herein. Therefore, the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

We claim:
 1. A compound of formula (II):

or a salt thereof, wherein: ring A is a fused ring that is selected fromthe group consisting of benzo and a 6-membered heterocycle; each R⁵ isindependently selected from the group consisting of C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(w))₂, —CN,—C(O)—N(R^(w))₂, —O—R^(w), —O—C(O)—R^(w), —C(O)—R^(x), and —C(O)O—R^(w),wherein any C₁₋₆alkyl, C₂₋₆alkenyl, and C₂₋₆alkynyl is optionallysubstituted with one or more oxo or halo; p is 0, 1, 2, 3, or 4; R⁶ is—N(R^(z))—C(O)—R^(x), 3-12 membered carbocycle, or a 3-12 memberedheterocycle, wherein each 3-12 membered carbocycle and 3-12 memberedheterocycle of R is optionally substituted with one or more groups R; Xis N or C(R⁷); R⁷ is H or C₁-C₆ alkyl that is optionally substitutedwith one or more groups independently selected from oxo and halo; eachR^(w) is independently selected from hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, 3-12 membered carbocyclyl, and 3-12 membered heterocyclyl,wherein each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, 3-12 memberedcarbocyclyl, and 3-12 membered heterocyclyl is optionally substitutedwith one or more groups independently selected from oxo, halo, amino,hydroxyl, C₁₋₆alkoxy, 3-12 membered carbocyclyl, 3-12 memberedheterocyclyl, and C₁-C₆ alkyl that is optionally substituted with one ormore groups independently selected from oxo and halo; or two R^(w) aretaken together with the nitrogen to which they are attached to form aheterocyclyl that is optionally substituted with one or more groupsindependently selected from oxo, halo and C₁₋₃alkyl that is optionallysubstituted with one or more groups independently selected from oxo andhalo; each R^(x) is independently selected from oxo, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, 3-12 membered carbocyclyl, 3-12 memberedheterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(y))₂, —CN, —C(O)—N(R^(y))₂,—S(O)—N(R^(y))₂, —S(O)₂—N(R^(y))₂, —O—R^(y), —S—R^(y), —O—C(O)—R^(y),—O—C(O)—O—R^(y), —C(O)—R^(y), —C(O)—O—R^(y), —S(O)—R^(y), —S(O)₂—R^(y),—O—C(O)—N(R^(y))₂, —N(R^(y))—C(O)—OR^(y), —N(R^(y))—C(O)—N(R^(y))₂,—N(R^(y))—C(O)—R^(y), —N(R^(y))—S(O)—R^(y), —N(R^(y))—S(O)₂—R^(y),—N(R^(y))—S(O)—N(R^(y))₂, and —N(R^(y))—S(O)₂—N(R^(y))₂, wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, 3-12 membered carbocyclyl, and 3-12membered heterocyclyl, is optionally substituted with one or more groupsindependently selected from oxo, halo, —NO₂, —N(R^(y))₂, —CN,—C(O)—N(R^(y))₂, —S(O)—N(R^(y))₂, —S(O)₂—N(R^(y))₂, —O—R^(y), —S—R^(y),—O—C(O)—R^(y), —C(O)—R^(y), —C(O)—O—R^(y), —S(O)—R^(y), —S(O)₂—R^(y),—C(O)—N(R^(y))₂, —N(R^(y))—C(O)—R^(y), —N(R^(y))—S(O)—R^(y),—N(R^(y))—S(O)₂—R^(y), 3-12 membered carbocycle, and C₁₋₆alkyl that isoptionally substituted with one or more groups independently selectedfrom oxo and halo; each R^(y) is independently selected from hydrogen,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, 3-12 memberedcarbocyclyl, and 3-12 membered heterocyclyl, wherein each C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, 3-12 membered carbocyclyl, and3-12 membered heterocyclyl is optionally substituted with one or moregroups independently selected from oxo, halo, amino, hydroxyl,C₁₋₆alkoxy, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, andC₁-C₆ alkyl that is optionally substituted with one or more groupsindependently selected from oxo and halo; or two R^(y) are takentogether with the nitrogen to which they are attached to form a 3-12membered heterocyclyl that is optionally substituted with one or moregroups independently selected from oxo, halo and C₁₋₃alkyl that isoptionally substituted with one or more groups independently selectedfrom oxo and halo; and each R^(z) is independently selected fromhydrogen, C₁₋₆alkyl.
 2. The compound or salt of claim 1, wherein thecompound is a compound of formula (IIa):


3. The compound or salt of claim 1, wherein the compound is a compoundof formula (IIb):


4. The compound or salt of claim 1, wherein the compound is a compoundof formula (IIc):


5. The compound or salt of claim 1, wherein the compound is a compoundof formula (IIe):


6. The compound or salt of claim 1, wherein X is N.
 7. The compound orsalt of claim 1 wherein X is C(R⁷).
 8. The compound or salt of claim 1,wherein R⁷ is H.
 9. The compound or salt of claim 1, wherein R⁷ isdifluoromethyl.
 10. The compound or salt of claim 1, wherein thecompound is a compound of formula (IIh):


11. The compound or salt of claim 1, wherein p is
 0. 12. The compound orsalt of claim 1, wherein R⁶ is a 3-12 membered heterocycle that isoptionally substituted with one or more groups R.
 13. The compound orsalt of claim 1, wherein R⁶ is selected from the group consisting of:

that is optionally substituted with one or more groups R^(x).
 14. Thecompound or salt of claim 1, wherein R⁶ is selected from the groupconsisting of:


15. The compound or salt of claim 1 selected from the group consistingof:

or a salt thereof.
 16. A pharmaceutical composition comprising acompound as described in claim 1 or a pharmaceutically acceptable saltthereof and a pharmaceutically acceptable adjuvant, carrier, or vehicle.17. A method for treating cancer, an inflammatory disorder, or anautoimmune disease in an animal comprising administering a compound asdescribed in claim 1 or a pharmaceutically acceptable salt thereof tothe animal.
 18. The method of claim 17 for treating cancer wherein thecancer is selected from acoustic neuroma, acute leukemia, acutelymphocytic leukemia, acute myelocytic leukemia, acute T-cell leukemia,basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer,breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma,chordoma, choriocarcinoma, chronic leukemia, chronic lymphocyticleukemia, chronic myelocytic leukemia, chronic myelogenous leukemia,colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma,diffuse large B-cell lymphoma, dysproliferative changes, embryonalcarcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelialcarcinoma, erythroleukemia, esophageal cancer, estrogen-receptorpositive breast cancer, essential thrombocythemia, Ewing's tumor,fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma,glioblastoma, gliosarcoma, heavy chain disease, head and neck cancer,hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitiveprostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer,lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia,lymphoma, lymphoid malignancies of T-cell or B-cell origin, medullarycarcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiplemyeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUTmidline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma,oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer,papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemiavera, prostate cancer, rectal cancer, renal cell carcinoma,retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma,seminoma, skin cancer, small cell lung carcinoma, solid tumors(carcinomas and sarcomas), small cell lung cancer, stomach cancer,squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroidcancer, Waldenstrom's macroglobulinemia, testicular tumors, uterinecancer, and Wilms' tumor.
 19. A method for treating a CBP and/orEP300-mediated disorder in an animal comprising administering a compoundas described in claim 1 or a pharmaceutically acceptable salt thereof tothe animal, wherein the CBP and/or EP300-mediated disorder is cancer,wherein the cancer is melanoma, NSCLC, renal cancer, ovarian cancer,colon cancer, pancreatic cancer, hepatocellular cancer, or breastcancer.
 20. The method of claim 19 further comprising the administrationof a cytotoxic agent to the animal.